The treatment landscape for melanoma is evolving rapidly with the introduction of novel therapies and combinations aimed at overcoming resistance and improving patient outcomes. Following the FDA's accelerated approval of lifileucel in February 2024, researchers are focused on building upon recent advancements to address the needs of patients who often experience resistance to available treatments. Omid Hamid, MD, Director of the Melanoma Program at Cedars Sinai, noted that novel agents and combinations are crucial for overcoming primary resistance, which affects a significant proportion (40%-50%) of patients undergoing initial checkpoint inhibitor therapy.
Lifileucel: A New Option for Advanced Melanoma
Lifileucel, a tumor-infiltrating lymphocyte (TIL) therapy, gained FDA approval for treating adult patients with unresectable or metastatic melanoma who have previously been treated with a PD-1 blocking antibody, and if BRAF V600 positive, a BRAF inhibitor with or without a MEK inhibitor. The approval was based on the phase 2 C-144-01 study, which demonstrated an objective response rate (ORR) of 31.5% (95% CI, 21.1%-43.4%) among efficacy-evaluable patients who received the recommended dose range. The median duration of response (DOR) was not reached, with 56.5%, 47.8%, and 43.5% of patients experiencing a DOR of at least 6, 9, or 12 months, respectively.
Further analysis of the C-144-01 trial revealed that patients who had undergone at least four prior lines of therapy achieved an ORR of 29.6% (95% CI, 18.0%-43.6%). Additionally, patients previously treated with an anti–CTLA-4 agent, anti–PD-1 plus anti–CTLA-4 combination therapy, or those who were primary refractory to anti–PD-(L)1 treatment, achieved ORRs of 32.8% (95% CI, 24.7%-41.8%), 26.8% (95% CI, 17.6%-37.8%), and 31.3% (95% CI, 21.6%-42.4%), respectively.
Combining Lifileucel with Pembrolizumab
Given the success of lifileucel monotherapy, investigators are exploring its combination with pembrolizumab as a frontline treatment for advanced melanoma in the phase 2 IOV-COM-202 study. Initial findings from cohort 1A of IOV-COM-202, which enrolled immune checkpoint inhibitor–naive melanoma patients, showed an ORR of 65.2% (95% CI, 42.7%-83.6%) and a complete response (CR) rate of 30.4%. These promising results have led to the initiation of the phase 3 TILVANCE-301 trial, comparing lifileucel plus pembrolizumab against pembrolizumab monotherapy in treatment-naive advanced melanoma patients. The coprimary endpoints of TILVANCE-301 are ORR and progression-free survival (PFS), with overall survival as a key secondary endpoint.
Investigating Novel Agents: IBI363
IBI363, a PD-1, IL-2α bispecific antibody, is also under investigation in a phase 1 trial involving patients with melanoma and other solid tumors. Early data presented at the 2024 European Society for Medical Oncology Virtual Plenary meeting indicated that melanoma patients who received prior immuno-oncology (IO) treatment achieved an ORR of 29.7% (95% CI, 15.9%-47.0%) and a disease control rate (DCR) of 73.0% (95% CI, 55.9%-86.2%). These findings led to the FDA granting fast track designation to IBI363 monotherapy for unresectable locally advanced or metastatic melanoma patients who progressed following at least one prior line of systemic treatment, including a PD-(L)1 inhibitor.
Personalized Cancer Vaccines: mRNA-4157 (V940)
The personalized cancer vaccine mRNA-4157 (V940) is being evaluated in combination with pembrolizumab in the phase 2b KEYNOTE-942 trial, which enrolled patients with completely resected stage IIIB to IV melanoma. Data from KEYNOTE-942 demonstrated an 18-month recurrence-free survival (RFS) rate of 79% (95% CI, 69.0%-85.6%) in the combination group compared to 62% (95% CI, 46.9%-74.3%) in the pembrolizumab monotherapy group. Treatment with V940 plus pembrolizumab resulted in a 44% reduction in the risk of disease recurrence or death (HR, 0.561; 95% CI, 0.309-1.017; 2-sided P = .053). A phase 3 trial (V940-001) is fully accrued and is examining the agent plus pembrolizumab vs pembrolizumab in the adjuvant setting.
TIL Therapy at MedStar Georgetown University Hospital
MedStar Georgetown University Hospital is among the first in the Washington metropolitan area to offer TIL therapy for metastatic melanoma. This approach involves using a patient's own tumor and immune system to fight the cancer. The TIL therapy process involves removing a melanoma tumor, extracting and expanding T-lymphocytes in the laboratory, and infusing these primed T-lymphocytes back into the patient to target and destroy cancer cells. Dr. Geoffrey Gibney, leader of the Melanoma Disease Group at MedStar Georgetown University Hospital, expressed excitement about offering this life-saving treatment, which provides a chance for durable, long-term responses in patients with advanced melanoma.
The Future of Melanoma Treatment
Ongoing research and clinical trials are continually refining melanoma treatment strategies. Experts emphasize the importance of personalized approaches, combining novel agents, and expanding the availability of effective therapies to improve outcomes for patients with this challenging disease.
