Editor's note: With the continuous emergence of new therapeutic drugs, the treatment of advanced melanoma has gradually developed from traditional chemotherapy and radiotherapy to immunotherapy, targeted therapy, chemotherapy and the combination of these treatments. For the first-line treatment options for advanced melanoma, researchers around the world are also constantly exploring and optimizing treatment options. At the 2024 American Society of Clinical Oncology Annual Meeting (ASCO 2024), several oral presentations of studies showcased the latest advances in this field. "Cancer Outlook" invited Professor Cui Chuanliang from Peking University Cancer Hospital to share these studies.
01
STUDY TITLE: The IOV-COM-202 study: a new breakthrough in the combination of TIL and immunotherapy in advanced melanoma
Although there has been significant progress with immune checkpoint inhibitors (ICIs) as first-line standard of care, many patients still fail to achieve long-term remission. The autologous tumor-infiltrating lymphocyte (TIL) therapy lifileucel has been approved by the US FDA for the option of immunotherapy progression, and the first-line treatment in combination with PD-1 monoclonal antibody provides a new therapeutic direction. This study evaluates the efficacy of lifileucel in combination with anti-PD-1 therapy in the first-line treatment of advanced melanoma. The IOVCOM-202(NCT03645928)1A cohort evaluates the efficacy and safety of lifileucel and pembrolizumab (pembro) in patients with unresectable or metastatic melanoma who are not treated with ICI[1].
BRAF mutation-positive patients who had previously received BRAF/MEK inhibitors were included. Patients need at least one resectable lesion for expansion culture of lifileucel and at least one measurable lesion for evaluation of treatment effect.
Treatment options include pembro, nonmyeloablative lymphodepletion (cyclophosphamide and fludarabine), a single lifileucel infusion, and IL-2 injections, with pembro continued for no more than 24 months in the absence of disease progression or acceptable toxicity. The study endpoints were objective response rate (ORR) and incidence of treatment-period adverse events (TEAEs).
As of December 22, 2023, a total of 23 patients have received this combination regimen. Baseline characteristics of patients: 7 patients (31.8%) had liver lesions; The metastatic stage at enrollment included: 2 cases (8.7%) had M0, 6 cases (26.1%) had M1a, 14 cases (60.9%) had M1b-M1d, and 1 case was unknown; Eight patients (34.8%) had BRAF V600 mutations; Three patients (13.0%) had been previously treated with BRAF/MEK inhibitors.
Treatment results showed an ORR of 65.2%, including 30.4% complete response (CR) and 34.8% partial response (PR). In addition, 26.1% of patients had stable disease (SD). All evaluable patients showed shrinkage of the target lesion and a deepening of the treatment response over time, with 66.7% of patients having sustained remission and 8 patients having a response time of at least 12 months.
△lifileucel + pembro shows long-lasting and deep relief
In terms of safety, TEAEs are consistent with known drug safety profiles. The most common grade 3 TEAEs ≥ included thrombocytopenia, neutropenia, and anemia (45.5%).
Results from the IOVCOM-202 Study 1A Cohort showed that lifileucel in combination with pembro demonstrated significant and durable efficacy in patients with untreated advanced melanoma. This finding supports further evaluation of the performance of this combination regimen in patients with untreated advanced melanoma in a phase III TILVANCE301 study. This advancement offers new hope for the treatment of patients with advanced melanoma and may change the treatment landscape of this disease in the future.
02
STUDY TITLE: The RELATIVITY-048 Study: The Potential of Triple Immunotherapy in Advanced Melanoma
Immunotherapy is an important treatment for advanced melanoma. Nivolumab (NIVO, anti-PD-1 antibody) as a single agent, or in combination with other immune checkpoint inhibitors, such as relatlimab (RELA, anti-LAG-3 antibody) and ipilimumab (IPI, anti-CTLA-4 antibody), have been approved abroad for the treatment of advanced melanoma. The RELATIVITY-048 study, a Phase I/II, non-randomized trial [2], presented for the first time at the ASCO Congress the efficacy of NIVO + RELA + IPI triple immunotherapy in patients with advanced melanoma.
In this study, patients with advanced melanoma were treated with NIVO 480 mg Q4W + RELA 160 mg Q4W + IPI 1 mg/kg Q8W first-line treatment until disease progression or unacceptable toxicity. The study allowed enrollment of patients who had completed frontline neoadjuvant/adjuvant therapy more than 6 months prior to enrollment, while also allowing patients with controlled brain metastases.
The primary endpoints of the study were safety and objective response rate (ORR), disease control rate (DCR), and median duration of response (DOR). The secondary endpoint is progression-free survival (PFS). The exploratory endpoint was overall survival (OS).
The results showed that among the 46 patients treated, the median follow-up was 44.1 months, and the median age of patients was 61.0 years. 8.7% of patients had acral cutaneous melanoma, 50.0% were BRAF-positive, 73.9% were LAG-3 positive, 26.1% were PD-L1 positive, and 6.5% had received adjuvant therapy. The median duration of treatment was 5.0 months. The ORR of triple immunotherapy was 58.7% and the 48-month OS rate was 69.1%.
△Survival data of patients in the RELATIVITY-048 study
In terms of safety, 95.7% of patients experienced treatment-related adverse events (TRAEs) of any grade, and 39.1% of patients experienced grade 3/4 TRAEs. 41.3% of patients discontinued treatment due to TRAE, and 2 patients died due to TRAE.
The RELATIVITY-048 study showed that NIVO + RELA + IPI showed good efficacy and safety, with positive results in both ORR and OS rates. However, more large-sample studies are still needed to further confirm the efficacy and safety of triple immunotherapy. This finding may provide a new treatment option for patients with advanced melanoma and provide a valuable reference for future clinical research and practice.
03
Study Title: The EBIN Study: Potential Benefit of Dual-Target + Dual-Free Sequential Therapy in Selected Patient Populations
BRAF inhibitors ± MEK inhibitors are important treatment options for the treatment of BRAF-V600E/K mutant advanced melanoma; The use of double immunity and dual targets in patients with mutations is still under study, and in the past, targeted induction therapy with BRAF + MEK inhibitors followed by combination with ipilimumab (Ipi) + nivolumab (Nivo) immunotherapy has been reported to be beneficial.
EBIN is an international randomized controlled phase II trial [3] that compared the efficacy and safety of this sequential therapy with direct immunotherapy. Patients were randomly assigned to 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 received three months of targeted therapy (Encorafenib 450 mg QD + Binimetinib 45 mg BID orally), followed by the same immunotherapy regimen as Group A. The primary objective of the study was to assess whether Group B demonstrated superiority in progression-free survival (PFS), with stratified subgroup analyses based on stage and lactate dehydrogenase (LDH) levels predefined.
A total of 136 patients in group B and 131/135 patients in group A were treated with the study regimen. At baseline, 170 (63 percent) patients had M1c disease, 129 (48 percent) had LDH above the upper limit of normal (ULN), 74 (27 percent) had liver metastases, and 19 (7 percent) received adjuvant therapy. The median follow-up was 21 months.
After a median follow-up of 21 months, the results showed that there was no significant difference in PFS between the two treatments in the intention-to-treat (ITT) population (HR 0.87, 90%CI: 0.67~1.12, P=0.36). However, in preset subgroup analyses, the HRs in 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: 0.54~1.29), 0.86 (95%CI: 0.54~1.37), and 0.46 (95% CI: 0.43~1.29), 0.86 (95%CI: 0.54~1.37), and 0.46 (95%) in group A for patients with stage III <≤ M0/M≤1a and LDH≤2ULN, and LDH>2ULN, respectively. CI: 0.21~1.03) (interaction P=0.044). For patients with high levels of LDH, PFS in the sequential treatment group showed a trend of benefit.
△EBIN study preset subgroup analysis
At the same time, in the post-hoc subgroup analysis, the HR of patients with liver metastases was 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.
△Post-hoc subgroup analysis of the EBIN study
In addition, the objective response rate (53% vs. 45%), complete response rate (12% vs. 10%), and ≥ grade 3 adverse event rate (43% vs. 32%) were comparable between groups B and A.
The EBIN study highlighted that there was no significant difference in PFS between the two treatments in unselected patients, but that specific patient populations, particularly those with high levels of LDH and liver metastases, may benefit from sequential treatment.
▌ References:
[1] Sajeve Samuel Thomas, Helen Gogas, Young Ki Hong, et al. Efficacy and safety of lifileucel, an autologous tumor-infiltrating lymphocyte cell therapy, and pembrolizumab in patients with immune checkpoint inhibitor-naive unresectable or metastatic melanoma: Updated results from IOV-COM-202 cohort 1A. ASCO 2024; Abstract 9505.
[2] Paolo Antonio Ascierto, Reinhard Dummer, Caroline Gaudy-Marqueste, et al. Efficacy and safety of triplet nivolumab, relatlimab, and ipilimumab (NIVO + RELA + IPI) in advanced melanoma: Results from RELATIVITY-048. ASCO 2024; Abstract 9504.
[3] Caroline Robert, Caroline Dutriaux, Felix Boakye Oppong, et al. Combination of encorafenib and binimetinib followed by ipilimumab and nivolumab versus ipilimumab and nivolumab in patients with advanced BRAF-V600E/K-mutated melanoma: The primary analysis of an EORTC randomized phase II study (EBIN). ASCO 2024; Abstract LBA9503.
Professor Cui Chuanliang
Doctor of Medicine, Chief Physician, Associate Professor, Master's Supervisor
Department of Melanoma and Urological Oncology, Peking University Cancer Hospital
Visiting scholar at the University of Pittsburgh Medical Center
Secretary of the CSCO Expert Committee on Urothelial Carcinoma
Member of the Standing Committee of the CSCO Melanoma Expert Committee
Member of the CSCO Young Expert Committee
Vice Chairman of the Head and Neck Melanoma Professional Committee of the Beijing Cancer Prevention and Control Society
Youth member of the Urogenital Tumor Professional Committee of Beijing Anti-Cancer Association
Mainly engaged in the medical treatment of melanoma and urologic tumors; Many papers have been published in Annals of Oncology, Annals of Surgical Oncology, JITC and other journals, and he has been responsible for and participated in a number of international and domestic multi-center clinical studies. As the main participant, he has won the second prize of Beijing Science and Technology Progress Award, the second prize of Science and Technology Progress Award of China Anti-Cancer Association, the third prize of Science and Technology Award of Chinese Medical Association, and the third prize of Huaxia Medical Award.