Lifileucel Paves the Way for Evolving Treatment Approaches After PD-1 Inhibition in Advanced Melanoma

Justin Moser, MD

The swath of agents and regimens approved for the first-line treatment of patients with advanced melanoma has muddied second-line treatment decision-making for this patient population, according to Justin Moser, MD, who added that past and ongoing clinical trials investigating immunotherapy strategies beyond checkpoint inhibition could help refine treatment strategies in this setting.

One agent currently indicated in the second-line space is lifileucel (Amtagvi), which received accelerated approval from the FDA in February 2024 for the treatment of adult patients with unresectable or metastatic melanoma previously treated with a PD-1 antibody, and if BRAF V600 positive, a BRAF inhibitor with or without a MEK inhibitor.

As mounting evidence suggests limited benefit from additional checkpoint blockade in patients previously unresponsive to dual checkpoint inhibition, concentrated efforts to diversify immunotherapy strategies via tumor-infiltrating lymphocyte (TIL) therapies such as lifileucel, T-cell receptor therapies, intratumoral agents, and cytokine-based approaches are gaining traction, Moser said.

“It is exciting that [the field] is beginning to move away from [the development of] novel checkpoint inhibitors,” Moser stated in an interview with OncLive®. “We’re starting to approach treatment-refractory melanoma [management] similarly to other tumor types such as ovarian cancer, where treatment decisions are informed by the [duration of response] or benefit [with prior therapy].”

In the interview, Moser discussed the limitations of current PD-1–based regimens for patients with primary or secondary resistance; the role of lifileucel in addressing unmet needs in advanced melanoma and factors influencing patient selection for this TIL therapy; and the ongoing exploration of alternative mechanisms of action to target during drug development for checkpoint-refractory disease.

Moser is a medical oncologist at HonorHealth and associate clinical investigator at HonorHealth Research Institute in Scottsdale, Arizona.

OncLive: What are some of the current advantages and limitations of anti–PD-1–based therapies in metastatic melanoma?

Moser: Immune checkpoint inhibitors—particularly PD-1–based treatments—have revolutionized the care of patients with melanoma. Prior to checkpoint inhibitors, the median survival for [advanced] melanoma was less than 6 months. Now, based on recent data, it is well over 7.5 years. It is clear that some patients are benefiting [from checkpoint inhibitors]. However, the patients who do not benefit from these therapies [represent] a significant unmet need.

What factors inform treatment decision-making for patients with advanced melanoma who respond poorly to, or are ineligible for, standard checkpoint inhibitor–based regimens?

When we look at people who initially progress on a combination of checkpoint inhibitors—whether [it be] nivolumab [Opdivo] plus ipilimumab [Yervoy] or nivolumab plus relatlimab-rmbw [Opdualag]—if those patients do not have a BRAF mutation, the most readily available treatment options are other checkpoint inhibitor combinations. How appropriate of an option that is depends on how well [patients] did on the initial combination. One of the challenges in melanoma is that the vast majority of the FDA-approved treatments that remain clinically relevant today are approved in the frontline setting. This means there is limited data to guide treatment in the second-line setting—without a clear frontline standard, there is also no standard for second-line treatment—making it difficult to determine the optimal next step.

Based on retrospective data, the likelihood of benefiting from a second-line checkpoint inhibitor–based combination appears to depend on the response to initial treatment. For people who initially respond to nivolumab plus relatlimab or nivolumab plus ipilimumab and then develop secondary resistance, there is an approximately 30% to 33% chance of responding to the other combination. When a patient presents with disease progression on a combination regimen, the first consideration is how they responded to the initial therapy, as this helps determine whether switching combinations is a reasonable approach.

For those who had no initial benefit from combination checkpoint inhibitors, the chance of responding to another checkpoint combination is likely 10% or less. In those cases, non–checkpoint inhibitor–based strategies are pursued, as these patients are likely resistant to checkpoint blockade and require therapies with a different mechanism of action.

How has the FDA approval of lifileucel affected the real-world treatment of patients with advanced melanoma who have progressed on prior immune checkpoint inhibitors?

[Lifileucel] has been slow to impact clinical practice. Lifileucel is a very intense therapy that requires involvement from multiple care team members and a multidisciplinary infrastructure. Although its adoption has increased, there was an initial delay in opening treatment centers. We have been operational since approximately April [2024] and have started using this therapy primarily for patients with primary resistance or those who have developed resistance to combination checkpoint inhibitors.

In the single-arm [phase 2 C-144-01] study [NCT02360579] that led to its approval, lifileucel demonstrated an objective response rate of 31.5% [95% CI, 21.1%-43.4%], with nearly half of responders experiencing durable responses lasting over 2 years. As is typical when a new treatment is approved in oncology, initial use often occurs in the sickest patients who have been awaiting new options the longest. Consequently, real-world outcomes may not immediately reflect the results seen in clinical trials. Over time, as lifileucel is administered earlier and in more appropriate clinical contexts, outcomes may improve.

Trial data have also indicated that patients with lower disease burden, [those being treated in] earlier lines of therapy, and [patients with] normal or lower lactate dehydrogenase [LDH] levels were more likely to benefit. Although not all patients respond [to this therapy, which is] consistent with all available cancer therapies, we have seen clinical benefit in patients previously treated with PD-1–based therapies, including some who had progressed on 3 to 5 prior lines of therapy.

What factors do you consider when determining if a patient is a candidate for lifileucel?

Not everyone is a candidate for lifileucel therapy. On average, approximately half of the patients referred for lifileucel are deemed ineligible, due to various factors. To generate the TIL product, a minimum [diameter] of 1.5 cm of tumor must be resected, meaning the tumor must be of sufficient size. With the FDA approval, the required number of cells for product generation increased, and product specifications were tightened. [In some cases], 2 to 3 cm of tumor may be required, and not all patients have resectable lesions of that size or lesions located in areas that can be safely excised.

Beyond tumor accessibility, patients must also be physically fit for therapy. Lifileucel requires lymphodepleting chemotherapy, which is more intensive than regimens used in CAR T-cell or T-cell receptor therapies. Patients must be candidates for both high-dose cytotoxic chemotherapy and high-dose interleukin-2 [IL-2]. Pre-treatment evaluation includes echocardiography to ensure adequate ejection fraction, pulmonary function testing, and performance status assessments.

However, patients who meet these objective criteria may still be unsuitable. In clinical experience, individuals over 70 years of age generally do not tolerate TIL therapy well. Thus, [we need to be] cautious with patient selection [for those over 70 years]. Functional status is another key determinant. Patients who are unable to walk a mile or climb a flight of stairs are not offered therapy until they can demonstrate the physical capacity to walk multiple miles continuously or ascend stairs. Optimal baseline fitness is essential to both tolerate therapy and recover post-treatment.

Has longer-term follow-up from the C-144-01 trial improved the identification of patients who may derive benefit from this TIL therapy? Could additional follow-up help further improve patient selection?

[Longer-term follow-up has highlighted some] of the same markers seen in the initial study—patients with lower-volume disease and normal LDH levels were more likely to benefit. This could be due to several reasons. Normal LDH and low disease burden are established predictors of response to various therapies in melanoma. Patients with these characteristics are more likely to respond to BRAF and MEK inhibitors if they have a BRAF mutation, as well as to checkpoint inhibitors.

These markers may be particularly important for TIL therapy. During surgery, the TILs harvested are specific to the tumor sample obtained. These T cells are expanded ex vivo and then reinfused. In patients with multifocal disease or high tumor burden, it is often not feasible to biopsy or resect every lesion. Although efforts are made to collect tissue from multiple sites, sampling is inherently limited—performing 20 lung biopsies or wedge resections is not practical.

As tumor burden increases, intratumoral heterogeneity also tends to increase. This presents a potential limitation for TIL therapy, as the infused lymphocytes may only recognize antigens expressed by the resected tumor site, but not by other lesions. This can result in mixed responses or partial responses, particularly in patients with more advanced or heterogeneous disease.

Are there any other ongoing clinical trials that could move the needle forward for patients with metastatic melanoma in the post–PD-1 inhibition setting?

We have a lot of phase 2 trials that have been completed or are ongoing in melanoma. RP1, an oncolytic injectable virus, is currently under FDA priority review [in combination with nivolumab, and has] a Prescription Drug User Fee Act date set for July [22, 2025]. [RP1] is a genetically modified virus similar to talimogene laherparepvec [T-VEC; Imlygic], but data [suggest] that it may offer improved efficacy and [has more] clinical advantages. [RP1 can be] administered at higher volumes, allowing greater tumor coverage, and it can be injected into deep lesions using CT-guided [imaging]. Although T-VEC has demonstrated efficacy in a select group of patients with melanoma, including some durable complete responses, its use has been limited by practical constraints. RP1 may broaden the population eligible for intratumoral viral therapy.

Additionally, the randomized phase 3 [SUPRAME trial (NCT06743126)] is evaluating a novel T-cell receptor therapy for melanoma. Genetically, engineered T-cell receptor therapies may offer enhanced potency compared with TIL therapy. [Unlike TIL, T-cell receptor] therapy does not require high-dose IL-2, which is responsible for much of the toxicity associated with TIL-based approaches, and TCR therapy can be administered with lower doses of chemotherapy. [However], the restriction with T-cell receptor therapy is that [patients] must be HLA-matched, limiting its applicability. [Still], phase 1 data showed a response rate of over 50% among patients with refractory melanoma.

Lastly, the ongoing randomized phase 3 [TEBE-AM trial (NCT05549297)] of tebentafusp-tebn [Kimmtrak] is investigating this agent in patients with refractory melanoma. Tebentafusp is also HLA-A*02:01–restricted, targeting a similar patient population. Phase 1b expansion data showed that tebentafusp may be effective in patients with melanoma who are refractory to dual immune checkpoint inhibition. For this patient population, rechallenge with checkpoint inhibitors is unlikely be beneficial, [highlighting] the need for therapies with novel mechanisms of action such as tebentafusp, T-cell receptor therapy, and RP1.

How do you see the post–PD-1 melanoma space continuing to evolve with additional research?

Although immune checkpoint inhibitors have revolutionized the field, we’re learning that [patients who are] dual checkpoint inhibitor–refractory are unlikely to benefit from further checkpoint inhibitor–based therapies. [A patient with melanoma] who responded to dual checkpoint inhibition for [at least] 6 months may reasonably be considered for another immunotherapy approach. However, for patients who received PD-1–based therapy and did not derive any meaningful benefit, we need new options and non–checkpoint inhibitor–based therapies.

[Although] later-stage therapies such as tebentafusp, [T-cell receptor] therapy, and RP1 are promising in this space, the early-phase pipeline is also active. [For example], cytokine-based therapies are another immunotherapy that do not overlap with checkpoint inhibitors. Novel delivery platforms—including prodrugs, intratumorally activated agents, and ‘immunokines’—are also being explored. In the next couple of years, we’re going to see some exciting data read out with these novel cytokines as well, which will just add another tool to our repertoire.

Reference

FDA approves first cellular therapy to treat patients with unresectable or metastatic melanoma. News release. FDA. February 16, 2024. Accessed February 16, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-first-cellular-therapy-treat-patients-unresectable-or-metastatic-melanoma