Lifileucel: A Novel Therapy for Metastatic Cutaneous Melanoma

Cutaneous melanoma is a type of skin cancer that originates from the melanocytes; in 2024, there have been 100,640 new diagnoses and 8290 melanoma-related deaths.¹ While it only accounts for about 1% of all skin cancers, it is responsible for the majority of skin cancer-related deaths.² Prognosis for cutaneous melanoma is affected by various factors including the thickness, ulceration, and mitotic rate of the tumor. For a localized melanoma that is 1 mm or less in thickness, the 5-year survival can be greater than 90%; however, for a melanoma with distant metastatic disease, the survival rate is less than 10%.³

Historically, treatment of metastatic melanoma has been limited to traditional chemotherapy agents such as dacarbazine, paclitaxel, and carboplatin, which have shown modest benefit in overall response. High dose intravenous IL-2 was also utilized; however, its use was limited to younger and fit patients due to the severity of serious adverse effects (AEs). The development of immune checkpoint inhibitors, including PD-1 inhibitors and CTLA-4 inhibitors, have revolutionized the treatment of metastatic melanoma. Oral small molecule inhibitors including BRAF inhibitors and MEK inhibitors have also been approved for patients with BRAF V600 mutations as well. However, many patients have early progression on these therapies with evidence of resistance to treatment.³ For these patients, there are lack of novel therapies available, leaving this patient population undertreated.

Historically, treatment of metastatic melanoma has been limited to traditional chemotherapy agents such as dacarbazine, paclitaxel, and carboplatin, which have shown modest benefit in overall response. Image Credit: © Shutter2U - stock.adobe.com

Lifileucel

On February 16, 2024, the FDA approved lifileucel (Amtagvi; Iovance LLC) for the treatment of adult patients with unresectable or metastatic melanoma previously treated with a PD-1 inhibitor and a BRAF inhibitor with or without a MEK inhibitor (for patients with a BRAF V600 mutation).⁴ The general information regarding the dose and administration of lifileucel is summarized below in Table 1.⁴

Lifileucel is a tumor-derived autologous T cell immunotherapy, offering a new mechanism of action to the treatment of metastatic melanoma. It is thought that while lifileucel is primarily composed of CD4+ and CD8+ T cells, it may also contain monocytes, B cells, NK cells, as well as melanoma tumor cells from the primary cancer. To further potentiate the cell expansion of the autologous T cell immunotherapy, IL-2 is also administered 3 to 24 hours after lifileucel infusion at 600 IU/kg every 8 to 12 hours with a maximum number of 6 doses.

Clinical Trial

The FDA approval of lifileucel was based on the results of a global, multicenter, multicohort, open-label, single arm trial (NCT02360579). This study included patients with unresectable or metastatic melanoma who have progressed on at least 1 systemic therapy including a PD-1 inhibitor and a BRAF with or without a MEK inhibitor (for patients with a BRAF V600 mutation). A total of 73 patients were included in the final analysis of the trial. Notable baseline characteristics of the patient population is outlined in Table 2.⁴ In addition, 54.8% of patients had brain and/or liver metastases.⁴

Efficacy of lifileucel was assessed through objective response rate (ORR) and duration of response (DoR). Out of the 73 patients who received lifileucel, the ORR was 31.5%, with a complete response of 3% and partial response of 20%. The median DoR was not achieved in the initial analysis of the trial with 56.5% of patients having DoR of 6 months or more, 47.8% of patients having DoR of 9 months or more and 43.5% of patients having DoR of 12 months or more. The median time to response of lifileucel was 1.5 months with a range of 1.3 to 4.2 months. For patients who showed response, 62.5%, 56.3%, and 54.2% of patients maintained a durable response at 6, 9, 12 months after the initial response to lifileucel therapy.4 In addition, a median of 6 doses of IL-2 were administered, though additional trials suggest that the number of doses of IL-2 does not impact the ORR of lifileucel.^4,5

Safety Considerations

Most common treatment-related AEs that were observed in the clinical trial is summarized in Table 3.

There are also several serious safety considerations with lifileucel. Lifileucel includes a warning of treatment-related mortality with 7.5% of patients having died due to therapy. Two deaths were reported during lymphodepleting chemotherapy, 6 deaths within 30 days of therapy, and 4 deaths within 38 to 150 days of therapy. Several AEs including life-threatening infections, internal hemorrhage, end organ failure, cardiac failure, and bone marrow failure have been some causes of treatment-related mortality.⁴

Grade 3 or higher cytopenia have also been observed in patients who have received lifileucel. In fact, 45.5% of patients had pancytopenia that did not resolve to grade 2 or less within 30 days of treatment as well. These cytopenia included pancytopenia (1.3%), neutropenia (17.3%), leukopenia (14.7%), lymphopenia (19.9%), and thrombocytopenia (30.1%). Patients receiving lifileucel should have their cell counts monitored closely after administration of therapy.⁴

Severe infections can also occur with lifileucel treatment. 26.9% of patients were observed with an infection due to treatment with 13.5% of patients with grade 3 or higher infection. While there is no standardized prevention of these infections, infection prophylaxis could be considered for these patients especially in those with prolonged cytopenia.⁴

Organ injury has also been observed with lifileucel. These include cardiac disorders (including arrhythmias, myocardial infarction, cardiomyopathy, and ventricular thrombosis), respiratory failure, and acute renal failure. All of these organ injuries and dysfunctions have been associated with death and patients should be closely monitored for these AEs.⁴

Discussion

The approval of lifileucel offers a novel mechanism of action of metastatic melanoma patients who have progressed on standard therapy with an immune checkpoint inhibitor or a BRAF inhibitor with or without a MEK inhibitor. While clinical trials have shown moderate objective response rate and duration of response, there are several safety concerns with lifileucel that needs to be considered prior to initiation of therapy. There is ongoing trials examining the combination of lifileucel with immune checkpoint inhibitors, which can expand the horizon of treatment of metastatic melanoma even further.⁶

REFERENCES

1. What Is Melanoma Skin Cancer? American Cancer Society. Last updated October 27, 2023. Accessed July 23, 2024. https://www.cancer.org/cancer/types/melanoma-skin-cancer/about/what-is-melanoma.html
2. Melanoma Skin Cancer Statistics. American Cancer Society. Last updated January 17, 2024. Accessed July 23, 2024. https://www.cancer.org/cancer/types/melanoma-skin-cancer/about/key-statistics.html
3. NCCN Guidelines Insights: Melanoma: Cutaneous, Version 2.2024. Journal of the National Comprehensive Cancer Network. 2024;22(5). doi:10.6004/jnccn.2024.0036
4. Amtagvi. Prescribing Information. Iovance Biotherapeutics Manufacturing LLC; 2024. Accessed July 23, 2024. https://www.fda.gov/media/176417/download
5. Hassel JC, Sarnaik A, Chesney J, et al. 35MO Number of IL-2 doses and clinical outcomes of tumor-infiltrating lymphocyte (TIL) cell therapy: Post hoc analysis of the C-144-01 trial of lifileucel in patients with advanced melanoma. Immuno-Oncol Technol. 2022;16. doi:10.1016/j.iotech.2022.100140
6. O’Malley D, Lee S, Psyrri A, et al. 492 Phase 2 efficacy and safety of autologous tumor-infiltrating lymphocyte (TIL) cell therapy in combination with pembrolizumab in immune checkpoint inhibitor-naïve patients with advanced cancers. J Immunother Cancer. 2021;9(suppl 2). doi:10.1136/jitc-2021-SITC2021.492