Editor’s Note: The 2023 European Society for Medical Oncology (ESMO) Annual Meeting took place in Madrid, Spain as scheduled. What new developments are there in the field of melanoma, which has attracted much attention? The oral presentations selected for the melanoma session focused on the challenges in melanoma treatment, including brain metastases, choroidal/mucosal melanoma, etc. “Tumor Outlook” invited Professors Su Lu and LiLi Mao from Peking University Cancer Hospital to provide a comprehensive interpretation, analyzing the clinical treatment challenges one by one.
01 Melanoma Brain Metastases
Intrathecal Injection—Tackling the Tougher Challenges Brain and spinal cord metastases in melanoma are undoubtedly among the most difficult challenges in the field. Even in the current era of burgeoning targeted and immune therapies, metastases to the central nervous system remain an area where many hesitate to tread. However, the melanoma research team from MD Anderson has persistently explored this area. In this ESMO meeting, they reported the latest results of intrathecal combined with intravenous injection of nivolumab (NIVO).
A total of 50 patients received treatment (48 with melanoma, 2 with non-small cell lung cancer), among whom 31 patients received intrathecal combined with intravenous injection of NIVO 50 mg. The median age at the time of diagnosis of central nervous system metastases was 49 years (range 19-74 years), with 27 male patients. All patients had radiological evidence of central nervous system metastases, and 26 patients were cytologically positive at baseline. Median follow-up and overall survival (OS) are shown in the table. Safety results were consistent with previous reports: 9 patients (18%) experienced Grade 3 adverse events (AE), with no Grade 4 or 5 AEs. Nausea (46%), rash (40%), vomiting (34%), diarrhea (20%), and dizziness (20%) were the most common AEs. Thirty patients (60%) experienced AEs after intrathecal injection, including 2 Grade 3 AEs (vasogenic edema, elevated ALT); the rest were Grade 1 or 2.
Conclusion: This latest analysis confirms the safety of intrathecal injection of NIVO (50 mg) combined with intravenous injection, with no significant difference in overall survival (OS) between the treatment groups, and no unexpected toxicity observed at the recommended dose. These results support further evaluation of intrathecal immunotherapy in patients with leptomeningeal metastases. Information obtained from the analysis of cerebrospinal fluid samples will contribute to the future development of intrathecal immunotherapy strategies for these patients
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Systemic Therapy – Exploring Up and Down
As early as 2017, three studies focused on brain metastases (ABC, checkmate204, combi-MB) laid the foundation for the significant role of dual targeting (BRAFi+MEKi) and dual immunotherapy (anti-CTLA-4+anti-PD-1) in the field of systemic therapy for brain metastases, achieving around 50% intracranial efficacy. In this ESMO conference, two studies also addressed systemic therapy for brain metastases: the TACo regimen (studying brain metastases following PD-1 failure) and the NIBIT-M2 study.
The TACo regimen consists of: atezolizumab (840 mg, IV, every 2 weeks), bevacizumab (5 mg/kg, every 2 weeks), and cobimetinib (60 mg, PO, once daily, for 3 weeks with a 1-week break). The rationale for this regimen is based on (1) VEGF promoting immune checkpoint blockade (ICB) resistance and (2) MEK inhibition increasing MHC I expression and T-cell infiltration, potentially synergizing with ICB.
The study results indicate that among 20 patients, 70% were male, with a median age of 59.5 years (34–78 years), and 2 patients had the BRAF V600E mutation. Eleven patients had previously received at least one line of treatment for melanoma brain metastases. The median follow-up was 8.2 months (0.4–39.2 months), and the median duration of treatment (DoT) was 8 weeks (0.6–63.8). Eighteen patients experienced treatment-related adverse events (AEs), with the most common being rash (70%), diarrhea (55%), hypertension (25%), and proteinuria (25%). Thirty-five percent of patients had grade 3/4 AEs, with hypertension (15%) and diarrhea (10%) being the most common. Two patients discontinued treatment due to toxicity. The intracranial efficacy could be evaluated in 18 patients, with an intracranial response rate of 39%, including 1 complete response (CR) and 6 partial responses (PR); the intracranial disease control rate was 56%, including stable disease (SD). The median progression-free survival (PFS) was 2.7 months (95% CI: 0.9–7.3), and the median overall survival (OS) was 9.3 months (95% CI: 3.8–20.9). Seven patients (35%) continued treatment for ≥3 weeks after progression (3–55 weeks).
Conclusion: In patients with melanoma brain metastases who have failed multiple lines of treatment and lack standard systemic treatment options, the TACo regimen is tolerable, demonstrates clinical benefits intracranially, and continues to provide sustained benefits after progression, warranting further evaluation.
Expert Commentary:
This small-sample study focuses on second-line treatment for patients with brain metastases who have failed PD-1 therapy, yet it still achieved a 39% intracranial response rate. For PD-1 resistant patients, especially those with toxicity contraindications to CTLA-4+PD-1 dual immunotherapy, this regimen may serve as an alternative. Additionally, bevacizumab may have a mitigating effect on brain edema, making the exploration of the TACo three-drug combination worthy of further investigation. However, the combination of MEK inhibitors with PD-1 is still controversial and requires further validation.
Another study is the NIBIT-M2 trial. This study, initiated in 2013 across nine centers in Italy, employed a three-group design to assess the efficacy of three drug combinations for asymptomatic brain metastases. Patients were randomized (1:1:1) to receive vemurafenib (F) alone (Group A), ipilimumab (I) + vemurafenib (Group B), or I + nivolumab (N) (Group C). This conference provided an update on the 7-year long-term survival and quality of life results of this study. From January 2013 to September 2018, a total of 80 patients were enrolled, with 76 receiving treatment: F (23 patients), I+F treatment (26 patients), and I+N treatment (27 patients). As of May 1, 2023, with a median follow-up of 67 months, the median overall survival (OS) for Groups A, B, and C were 8.5 (95% CI: 6.6–10.3), 8.2 (95% CI: 2.1–14.3), and 29.2 (95% CI: 0–69.9) months, respectively. The 7-year OS rates were 10.0% (95% CI: 0–22.5) for Group A, 10.3% (95% CI: 0–22.6) for Group B, and 42.8% (95% CI: 23.4–62.2) for Group C. The median intracranial progression-free survival (iPFS) for Groups A, B, and C were 3.0 (95% CI: 2.3–3.6), 3.3 (95% CI: 1.2–5.4), and 8.7 (95% CI: 0–19.9) months, respectively. The 7-year iPFS rates were 4.3% (95% CI: 0–12.7) for Group A, 7.7% (95% CI: 0–17.9) for Group B, and 28.6% (95% CI: 11.2–46.0) for Group C. Seventy-two patients (95% compliance) and 34 patients (45% compliance) completed baseline and 12-week QLQ C-30 assessments. Patients in all treatment groups maintained high health-related quality of life (HRQoL), with no significant differences in overall health scores among the groups. Most functional scale scores remained stable from baseline to 12 weeks, with only a slight decrease in average scores for patients receiving I+N treatment.
Conclusion: The 7-year results of the NIBIT-M2 study represent the longest follow-up to date for asymptomatic brain metastases in melanoma patients receiving I+N treatment, continuing to demonstrate sustained efficacy. HRQoL was maintained in all treatment groups, with a slight decline in average scores for patients receiving I+N treatment.
Expert Commentary:
The NIBIT-M2 study is a randomized controlled trial conducted in multiple centers in Italy, focusing on brain metastases. Vemurafenib has been approved in Europe for the treatment of advanced melanoma, and previous studies have shown its efficacy in brain metastases. Hence, it was chosen as the control group in this study. After 7 years of long-term follow-up, the results show that the PFS and OS of the dual immunotherapy group are superior to the other two groups. Regarding quality of life, the dual immunotherapy group had slightly lower scores, but there was no significant difference among the three groups. The results of this study once again confirm the benefits of dual immunotherapy for brain metastases. The question that remains is, if dual immunotherapy fails, what treatment options are available? Is vemurafenib worth trying? We still need more evidence from evidence-based medicine.
Brain Metastasis Prevention – Treating Before the Disease Occurs
The SECOMBIT study is a classic exploration of the sequential order of targeted therapy and immunotherapy in the BRAF mutation population. Patients were randomized into three groups: Group A received encorafenib/binimetinib (E+B) targeted combination therapy as first-line treatment, followed by ipilimumab/nivolumab (I+N) treatment upon progression; Group B received I+N immunotherapy as first-line treatment, followed by E+B treatment upon progression; and a “sandwich” Group C received immunotherapy after eight weeks of dual-targeted treatment, followed by a return to targeted therapy upon progression. All patients in the study had BRAF mutations, which are associated with a higher incidence of brain metastases. This ESMO conference reported the incidence of brain metastases in the three groups. Compared to patients in Group A, those in Groups B and C had a reduced risk of developing brain metastases. During the first-line treatment phase, the number of patients developing brain metastases in Groups A, B, and C were 17, 6, and 8, respectively. Throughout the study, 23, 11, and 9 patients in Groups A, B, and C, respectively, were detected with intracranial progression. The exploratory hazard ratio (HR) for brain metastasis-free survival (BMFS) in Group B compared to Group C was 0.51 (0.25–1.04), and in Group C compared to Group A was 0.37 (0.17–0.81). Biomarker analysis showed that patients with high tumor mutation burden (TMB, ≥10 mut/mb) had better BMFS [HR 0.20 (0.05–0.95)] than those with low TMB. Patients with JAK mutations also had better BMFS compared to wild-type patients [HR 0.26 (0.06–1.12)]. Conclusion: Patients in Groups B and C had longer BMFS compared to those who received targeted therapy first. Patients with high TMB and JAK mutations had higher 4-year BMFS rates.
Expert Commentary:
The SECOMBIT study, addressing the long-debated issue of the sequence of targeted therapy and immunotherapy, has taken the lead in exploration. Both the previously reported survival data and the newly reported brain metastasis data suggest that the immunotherapy-first approach in Groups B and C seems more favorable. However, in clinical practice, patients who experience early recurrence/metastasis/progression during immunotherapy often still carry BRAF mutations. Therefore, immunotherapy may not be the optimal solution for BRAF-mutant patients. Instead of getting stuck in the age-old debate of who comes first, it may be more fruitful to explore new perspectives. Of course, the challenge of backline treatment for BRAF mutations remains a difficult problem.
Choroidal/Mucosal Melanoma
Choroidal Melanoma — A New Dawn in the Darkness Ninety-five percent of choroidal melanoma (CM) patients carry driver mutations in GNAQ/11, activating the protein kinase C (PKC) signaling pathway. Darovasertib (IDE196, Daro) is an oral PKC inhibitor, and preliminary studies have shown its clinical efficacy in metastatic choroidal melanoma (MUM). Crizotinib is an oral c-MET inhibitor that has demonstrated synergistic effects with Daro in preclinical studies. This conference reported results from a Phase 1/2 study evaluating the effectiveness of this combination in both treatment-naive and previously treated MUM patients.
As of March 8, 2023, 68 MUM patients (Safety Population, SP) received extended-dose treatment. As of September 2022, 63 patients with assessable efficacy (Protocol Efficacy Evaluation Population, PPEP) were included. The PPEP had a substantial tumor burden: 66% of patients had the largest metastatic lesion >3 cm, 64% had liver with extrahepatic lesions, and 60% had elevated LDH levels. HLA-A2*02:01 status (tested in n=51): 63% were negative. In the SP, the most common drug-related adverse events (AEs, >30%) were diarrhea, nausea, edema, fatigue, hypotension, and rash. AEs were mainly grades 1-2. Six patients (9%) experienced severe treatment-related AEs, leading to treatment discontinuation in 4 patients. In the PPEP, 30% of patients achieved confirmed partial response (cPR), and 92% of patients had tumor shrinkage. The cPR for treatment-naive patients (n=20) was 45%, with tumor shrinkage observed in 95% of patients. The median progression-free survival (mPFS) for both PPEP and treatment-naive patients was 7 months. In patients with liver-only disease (20 cases, both treatment-naive and previously treated), the overall response rate was 35%, and mPFS was 11 months. Clinical efficacy was observed in HLA-A2-positive and negative patients. Most patients exhibited deep and sustained ctDNA molecular responses.
Conclusion: The preliminary assessment of Daro+Crizo in treatment-naive and previously treated MUM patients demonstrates manageable safety and clinical efficacy, appearing to be superior to current standard treatments. Almost all patients showed a reduction in ctDNA. These data support the initiation of Phase II/III registration studies in first-line MUM patients who are HLA-A2 negative, with the hope of accelerating approval. Currently, there is no FDA-approved treatment in this field.
Expert Commentary:
In 2022, tebentafusp became the first drug approved by the FDA for advanced choroidal melanoma. However, its efficacy is not outstanding, and its approval is mainly due to the survival benefit it provides. Additionally, tebentafusp requires HLA typing, limiting its use to patients with HLA-A2 01, thus excluding many patients from this treatment option. Unfortunately, most choroidal melanoma patients carry GNAQ/11 mutations, and there is no targeted therapy for this mutation. Darovasertib (IDE196), reported in this study, is an oral PKC inhibitor acting downstream of G-proteins. However, Darovasertib as a monotherapy has a low response rate (9.1%), but the combination with a c-MET inhibitor, as reported in this study, achieved a response rate of 30%, significantly higher than other regimens in choroidal melanoma. This result warrants further exploration.
Mucosal Melanoma — Riding the East Wind with Frenzy
Lifileucel is a single-dose autologous tumor-infiltrating lymphocyte (TIL) therapy that, in the C-144-01 study (NCT02360579), achieved a 31.4% objective response rate (ORR) in 153 patients who had failed multiple treatments. This conference reported the results of late-stage mucosal melanoma (MM) patients using lifileucel from the C-144-01 study.
The study included 15 MM patients, all of whom successfully received lifileucel, with lymph nodes being the most common specimen source (47%). Twelve patients underwent lifileucel treatment. Median target lesion sum of diameters: 118.9 mm; median prior treatments: 2 lines (range: 1–6); LDH > ULN: 42%; liver and/or brain metastases: 42%. The median TIL infusion was 26 × 10^9 cells. The ORR was 50% (95% CI: 21%–79%). At a median follow-up of 35.7 months, median duration of response (DOR) not reached (NR; 95% CI: 12.5–NR), median progression-free survival (PFS) NR (95% CI: 1.4–NR), and median overall survival (OS) 19.4 months (95% CI: 7.9–NR) were observed. Treatment-related adverse events (TEAE) were consistent with known safety profiles of lymphodepletion chemotherapy and IL-2. The most common (30%) grade 3/4 non-hematologic TEAEs were febrile neutropenia (58%) and hypotension (33%).
Conclusion: In the C-144-01 study, lifileucel demonstrated significant and durable clinical activity (ORR: 50%; median DOR: NR) in refractory MM patients who had failed PD-1/PD-L1 therapy. These data support the potential benefit of lifileucel as a single-dose therapy.
Expert Commentary:
TIL therapy is not a new treatment modality, and technological advancements are driving improvements in TIL techniques. Lifileucel is a TIL therapy developed by Iovance Biotherapeutics using TIL technology introduced from the National Institutes of Health (NIH) in the United States. LN-144 is produced using a third-generation process, with a TIL cell culture expansion time of 16 days. This report from the C-144-01 Phase II study in late-stage mucosal melanoma patients shows a response rate of 50%, indicating promise in the mucosal subtype. It is noteworthy that the FDA has accepted the biologics license application (BLA) for lifileucel for the treatment of advanced melanoma, with the final approval expected on November 25, 2023.
Additionally, an oral presentation at this ESMO conference discussed the 7-year follow-up results of the CheckMate 238 study, continuing to show the superiority of the NIVO group over the IPI group, making it the longest follow-up time in patients receiving ICI adjuvant therapy.
This ESMO conference has brought more attention to the field of refractory melanoma, including brain metastases, choroidal melanoma, and more. We look forward to more research focusing on challenges and breakthroughs in these difficult-to-treat areas.
References :
- Isabella C. Glitza, et al. Concurrent intrathecal (IT) and intravenous (IV) nivolumab (N) for melanoma (MM) patients (pts) with leptomeningeal disease (LMD). ESMO 2023; abstract 1082O.
- Elizabeth Burton, et al. Atezolizumab, bevacizumab, and cobimetinib (TACo) in patients (pts) with PD1 refractory melanoma brain metastases (MBM). ESMO 2023; abstract 1085O.
- Anna M. Di Giacomo, et al. Nivolumab plus ipilimumab in melanoma patients with asymptomatic brain metastases: 7-year outcomes and quality of life from the multicenter phase III NIBIT-M2 trial. ESMO 2023; abstract 1084MO.
- Paolo A. Ascierto, et al. Brain metastases and survival evaluation in the SECOMBIT trial. ESMO 2023; abstract 1083MO.
- Meredith Mckean, et al. ctDNA reduction and clinical efficacy of the darovasertib + crizotinib (daro + crizo) combination in metastatic uveal melanoma (MUM). ESMO 2023; abstract 1081O.
- Evidio Domingo-Musibay, et al. Lifileucel tumor-infiltrating lymphocyte (TIL) cell therapy in patients (pts) with advanced mucosal melanoma after progression on immune checkpoint inhibitors (ICI): Results from the phase II C-144-01 study. ESMO 2023; abstract 1086MO.
Professor Lu Si
Chief Physician, Department of Melanoma and Sarcoma, Peking University Cancer Hospital, Ph.D. Supervisor
Author of “CSCO Guidelines for the Diagnosis and Treatment of Melanoma”
Author of “CSCO Guidelines for the Management of Toxicities Related to Immune Checkpoint Inhibitors”
Deputy Director of the CSCO Melanoma Expert Committee
Deputy Director of the CSCO Neuro-Oncology Special Committee
Young Editorial Board Member and Deputy Editor-in-Chief of the Journal of Oncology
Expert Reviewer for Clinical Cancer Research
Professor Mao Lili
Associate Chief Physician, Department of Renal Cancer and Melanoma, Beijing Cancer Hospital, Ph.D.
Secretary of the Melanoma Expert Committee, Chinese Society of Clinical Oncology (CSCO)
Member of the Youth Committee, Tumor Clinical Chemotherapy Professional Committee, Chinese Anti-Cancer Association (CACA)
Visiting Scholar at the Sydney University Westmead Hospital Oncology Center and the Melanoma Institute Australia (MIA)
