SUMMARY: The American Cancer Society estimates that in 2022, about 99,780 new cases of melanoma of the skin were diagnosed in the United States and 7,650 people died of the disease. The rates of melanoma have been rising rapidly over the past few decades, but this has varied by age.
Immunotherapy with Immune Checkpoint Inhibitors (ICIs) has revolutionized cancer care and has become one of the most effective treatment options by improving Overall Response Rate (ORR) and prolongation of survival across multiple tumor types. These agents target Programmed cell Death protein-1 (PD-1), Programmed cell Death Ligand-1 (PD-L1), Cytotoxic T-Lymphocyte-Associated protein-4 (CTLA-4), and many other important regulators of the immune system. YERVOY® (Ipilimumab) is a fully human immunoglobulin G1 monoclonal antibody that blocks Immune checkpoint protein/receptor CTLA-4, and was the first systemic therapy in randomized Phase III trials, to show prolonged Overall Survival (OS) in patients with advanced melanoma. The two PD-1 inhibitors of interest are OPDIVO® (Nivolumab) and KEYTRUDA® (Pembrolizumab), which are fully human, Immunoglobulin G4, anti-PD-1 targeted monoclonal antibodies that bind to the PD-1 receptor, and block its interaction with ligands PD-L1 and PD-L2, following which the tumor-specific effector T cells are unleashed. They are thus able to undo PD-1 pathway-mediated inhibition of the immune response. When compared with YERVOY® in patients with advanced melanoma, PD-1 inhibitors, both OPDIVO® and KEYTRUDA® have demonstrated superior Overall Survival (OS), Progression Free Survival (PFS), and Objective Response Rate (ORR), with a better safety profile. They are therefore frequently used first-line treatment in patients with metastatic melanoma.
Over 50% of untreated patients receiving a combination of PD-1 and CTLA-4 inhibitors are alive after five years. However, combination immunotherapy with YERVOY® and OPDIVO® is associated with a high incidence of severe adverse events and is currently recommended primarily for a subgroup of patients with poor prognostic factors such as a high serum LDH levels or liver or brain metastases. Approximately 50% of melanomas harbor BRAF V600E mutation and are often treated with a combination of BRAF and MEK inhibitors. This combination is associated with a high response, but resistance develops in most patients over time. YERVOY® is presently often used as second line therapy, but only 15-30% of patients benefit from this intervention. There is an unmet need for this group of patients.
Adoptive immunotherapy, also known as cellular immunotherapy, is a form of treatment in which naturally occurring or gene-engineered T cells with antitumor activity are transferred to a tumor-bearing host to eliminate cancer. These killer T cells bind to antigens on the surface of cancer cells and destroy them. Cellular immunotherapies include Tumor-Infiltrating Lymphocyte (TIL) Therapy, Engineered T Cell Receptor (TCR) Therapy, Chimeric Antigen Receptor (CAR) T Cell Therapy and Natural Killer (NK) Cell Therapy.
Adoptive immunotherapy with Tumor-Infiltrating Lymphocytes (TILs) is a personalized autologous therapy in which lymphocytes which have infiltrated the tumor are expanded in vitro and administered intravenously following nonmyeloablative, lymphodepleting chemotherapy, and supported by the IV administration of Interleukin-2 (IL-2) to enhance the in vivo expansion of the cells and augment antitumor responses. In contrast to Lymphokine-Activated Killer cells (LAK), human TILs demonstrate cytolytic specificity against only the tumor from which they were derived or against closely related tumors, and in preclinical models have proved to be 50 to 100 times more potent than LAK cells. Evidence of clinical activity of TIL therapy in patients with advanced melanoma was initially reported by Rosenberg and colleagues in the 1990s and subsequent Phase 1-2 trials showed responses in 30-70% of patients, with responses noted even among those who had disease progression while receiving anti-PD1 treatment. Nonetheless, there has been no direct comparison of TILs with standard treatment.
This multicenter, open-label, Phase III, randomized trial was conducted to compared TILs with Yervoy® as first or second-line treatment in patients with advanced melanoma. In this study, a total of 168 patients with unresectable Stage IIIC or IV melanoma were randomly assigned in a 1:1 ratio to receive either TILs (N=84) or YERVOY® (N=84). Patients assigned to receive TILs underwent metastasectomy for the retrieval and expansion of TILs, followed by inpatient administration of nonmyeloablative, lymphodepleting chemotherapy, which consisted of Cyclophosphamide 60 mg/kg IV QD for 2 days and Fludarabine 25 mg/m2 IV QD for 5 days, single adoptive transfer of 5×109 to 2×1011 TILs intravenously, and subsequent high-dose IL-2, 600,000 IU/kg IV every 8 hours, for a maximum of 15 doses. Patients in the YERVOY® group received 3 mg/kg IV every 3 weeks, for a maximum of 4 doses. Administration of YERVOY® could be delayed or discontinued if adverse events occurred, and no dose reductions were allowed. Both treatment groups were well balanced and 86% of patients were refractory to PD-1 inhibitor therapy, mostly adjuvant or first line therapy. The median patient age was 59 years and patients were stratified according to BRAF V600-mutation status, line of treatment, and treatment center. The Primary end point was Progression Free Survival (PFS). Secondary end points included Objective Response Rate (ORR), Complete Response (CR), Overall Survival (OS), Health-Related Quality of Life and Safety.The median follow-up was 33.0 months.
The median PFS was 7.2 months in the TIL group and 3.1 months in the YERVOY® group (HR=0.50;P<0.001).The Objective Response Rate was 49% in the TIL group and 21% in the YERVOY® group, with a Complete Response rate of 20% in the TIL group and 7% in the YERVOY® group, with durable Complete Responses in both treatment groups. The median Overall Survival was 25.8 months in the TIL group and 18.9 months in the YERVOY® group(HR=0.83). The 2-year OS was 54.3% in the TIL group and 44.1% in the YERVOY® group. Treatment-related adverse events of Grade 3 or higher occurred in all patients in the TIL group and in 57% of those in the YERVOY® group, and these events were mainly chemotherapy-related myelosuppression. Treatment-related serious adverse events occurred in 15% of the patients in the TIL group and 27% of those in the YERVOY® group.
It was concluded that in patients with advanced melanoma including those patients refractory to PD-1 inhibitor therapy, treatment with TILs was associated with significantly longer Progression Free Survival than treatment with YERVOY®.
Tumor-Infiltrating Lymphocyte Therapy or Ipilimumab in Advanced Melanoma. Rohaan MW, Borch TH, Van den Berg JH, et al. N Engl J Med 2022; 387:2113-2125
