Editor's Note: With the continuous emergence of novel therapeutic agents, treatment strategies for advanced melanoma have evolved from traditional chemotherapy and radiotherapy to include immunotherapy, targeted therapy, chemotherapy, and their combinations. Global researchers are constantly exploring and optimizing treatment options for first-line therapy in advanced melanoma. At the 2024 American Society of Clinical Oncology (ASCO 2024) Annual Meeting, several oral presentations showcased the latest developments in this field. Oncology Frontier is honored to have Professor Chuanliang Cui from Peking University Cancer Hospital share insights on these studies.

Study Title: IOV-COM-202 Study: TIL Combined Immunotherapy Breakthrough in Advanced Melanoma

Despite significant advancements in first-line standard treatment with immune checkpoint inhibitors (ICI), many patients fail to achieve long-term relief. Autologous tumor-infiltrating lymphocyte (TIL) therapy lifileucel has been FDA-approved for salvage immunotherapy, offering a new treatment direction when combined with PD-1 monoclonal antibodies. This study evaluates the efficacy of lifileucel combined with anti-PD-1 therapy as first-line treatment for advanced melanoma. The IOVCOM-202 (NCT03645928) 1A cohort assessed the efficacy and safety of lifileucel and pembrolizumab in untreated, unresectable, or metastatic melanoma patients who had previously received BRAF/MEK inhibitor therapy. Patients required at least one resectable lesion for lifileucel expansion culture and at least one measurable lesion for treatment evaluation.

The treatment regimen included pembrolizumab, non-myeloablative lymphocyte depletion (cyclophosphamide and fludarabine), a single infusion of lifileucel, and IL-2 injection, with pembrolizumab continued for up to 24 months in the absence of disease progression or acceptable toxicity. Study endpoints included objective response rate (ORR) and incidence of treatment-emergent adverse events (TEAE).

As of December 22, 2023, a total of 23 patients underwent this combination therapy. Baseline characteristics included liver lesions in 7 patients (31.8%); metastatic staging at enrollment included 2 cases (8.7%) M0, 6 cases (26.1%) M1a, 14 cases (60.9%) M1b-M1d, and 1 unknown; 8 patients (34.8%) had BRAF V600 mutations; and 3 patients (13.0%) had prior BRAF/MEK inhibitor therapy. Treatment outcomes demonstrated an ORR of 65.2%, comprising 30.4% complete responses (CR) and 34.8% partial responses (PR). Additionally, 26.1% of patients experienced stable disease (SD). All evaluable patients showed reduction in target lesions, with treatment responses deepening over time, and 66.7% of patients achieving sustained remission, with a minimum duration of 12 months for 8 patients.

Key Insight: Lifileucel + pembrolizumab exhibited durable and profound remissions. In terms of safety, TEAEs were consistent with known drug safety profiles, with the most common ≥ Grade 3 TEAEs including thrombocytopenia, neutropenia, and anemia (45.5%).

Results from the IOVCOM-202 Study 1A cohort highlight significant and durable efficacy of lifileucel combined with pembrolizumab as first-line treatment in untreated advanced melanoma patients. This finding supports further evaluation of this combination therapy in the Phase III TILVANCE301 study among untreated advanced melanoma patients, providing new therapeutic hope and potentially altering the treatment landscape for this disease.

Study Title: RELATIVITY-048 Study: Potential of Triple Immunotherapy in Advanced Melanoma

Immunotherapy plays a critical role in the treatment of advanced melanoma. Monotherapy with nivolumab (NIVO, anti-PD-1 antibody), or in combination with other immune checkpoint inhibitors such as relatlimab (RELA, anti-LAG-3 antibody) and ipilimumab (IPI, anti-CTLA-4 antibody), has been approved internationally for treating advanced melanoma. The RELATIVITY-048 study, a Phase I/II non-randomized trial, presented for the first time at this ASCO meeting, assessed the application of NIVO + RELA + IPI triple immunotherapy in patients with advanced melanoma.

In this study, patients with advanced melanoma received first-line treatment with NIVO 480 mg Q4W + RELA 160 mg Q4W + IPI 1 mg/kg Q8W until disease progression or unacceptable toxicity. The study allowed enrollment of patients who had completed frontline neoadjuvant/adjuvant therapy more than 6 months before enrollment, as well as patients with controlled brain metastases.

The primary endpoints were safety, objective response rate (ORR), disease control rate (DCR), and median duration of response (DOR). Secondary endpoints included progression-free survival (PFS) and exploratory endpoints for overall survival (OS).

Results showed that among 46 treated patients, with a median follow-up of 44.1 months and a median age of 61.0 years, 8.7% had acral cutaneous melanoma, 50.0% were BRAF positive, 73.9% were LAG-3 positive, 26.1% had tumor cell PD-L1 positivity, and 6.5% had received adjuvant therapy. The median duration of treatment was 5.0 months. The triple immunotherapy ORR was 58.7%, with a 48-month OS rate of 69.1%.

Key Insight: RELATIVITY-048 Study demonstrates favorable efficacy and safety of NIVO + RELA + IPI, showing positive results for ORR and OS rates. Further large-sample studies are required to confirm the efficacy and safety of triple immunotherapy. This finding may provide a new treatment option for patients with advanced melanoma and valuable reference for future clinical research and practice.

Study Title: EBIN Study: Potential Benefits of Sequential Dual-Target + Dual-Immune Therapy in Specific Patient Populations

For BRAF-V600E/K mutant advanced melanoma, BRAF inhibitors ± MEK inhibitors are important treatment options. The sequential use of dual immune checkpoint inhibitors and dual targeting agents in mutation-positive patients is still under investigation. Previous reports have shown potential benefits of receiving BRAF+MEK inhibitor targeted induction therapy followed by ipilimumab (IPI) + nivolumab (NIVO) immunotherapy.

EBIN is an international Phase II randomized controlled trial comparing the efficacy and safety of sequential therapy versus direct immunotherapy in these patients. Patients were randomized into two treatment groups: Group A received direct immunotherapy (NIVO 3 mg/kg + IPI 1 mg/kg q3w x4, followed by NIVO 480 mg q4w), while Group B underwent three months of targeted therapy (Encorafenib 450 mg QD + Binimetinib 45 mg BID orally), followed by the same immunotherapy regimen as Group A. The study’s primary objective was to evaluate whether Group B demonstrated superior efficacy in progression-free survival (PFS) compared to Group A, with pre-specified subgroup analyses based on staging and lactate dehydrogenase (LDH) levels.

A total of 136 Group B patients and 131/135 Group A patients received the study treatment. At baseline, 170 patients (63%) were M1c stage, 129 patients (48%) had LDH above the upper limit of normal (ULN), 74 patients (27%) had liver metastases, and 19 patients (7%) had received adjuvant therapy. The median follow-up was 21 months.

After a median follow-up of 21 months, results showed no significant difference in PFS between the two treatment methods in the intention-to-treat (ITT) population (HR 0.87, 90% CI: 0.67–1.12, P=0.36). However, in pre-specified subgroup analyses, for Stage III patients with M0/M1a and LDH≤ULN, M1b/M1c and LDH≤ULN, ULN<LDH≤2ULN, and LDH>2ULN, the HR for Group B vs. Group A were 2.09 (95% CI: 0.97–4.54), 0.74 (95% CI: 0.43–1.29), 0.86 (95% CI: 0.54–1.37), and 0.46 (95% CI: 0.21–1.03) respectively (interaction P=0.044). There was a trend towards PFS benefit in LDH high-level patients in the sequential treatment group.

Moreover, in post hoc subgroup analysis, patients with liver metastases had a treatment HR of 0.49 (95% CI: 0.29–0.84, interaction P=0.013). Patients with liver metastases in the sequential treatment group also showed a trend towards PFS benefit.

Additionally, Group B and Group A had comparable objective response rates (53% vs. 45%), complete response rates (12% vs. 10%), and ≥ Grade 3 adverse event rates (43% vs. 32%).

Key Insight: EBIN Study emphasizes that in unselected patients, there was no significant difference in PFS between the two treatment methods, but specific patient populations, particularly those with high LDH levels and liver metastases, may benefit from sequential dual-targeted and dual-immune therapy.

Conclusion

The 2024 ASCO Annual Meeting provided a platform for presenting several studies exploring new first-line treatment options for advanced melanoma. The IOV-COM-202 Study demonstrated that the combination of lifileucel and pembrolizumab as first-line treatment in advanced melanoma showed significant and durable efficacy. In addition, the RELATIVITY-048 Study showed that triple immunotherapy with NIVO + RELA + IPI exhibited a favorable response rate and overall survival rate. In addition, the EBIN Study found that patients with high LDH levels and liver metastases may benefit from sequential dual-targeted and dual-immune therapy.

As a key part of the 2024 ASCO Annual Meeting, these studies may help reshape the first-line treatment landscape for advanced melanoma, providing new therapeutic options and improving patient outcomes.