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On April 26-27, 2024, the 2024 CSCO Guidelines Meeting, co-sponsored by the Chinese Society of Clinical Oncology (CSCO) and Beijing Heath Clinical Oncology Research Foundation, was held in Jinan. In the melanoma session, Professor Chen Jing from Union Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology, Professor Mao Lili from Peking University Cancer Hospital and Professor Chen Yu from Fujian Provincial Cancer Hospital respectively interpreted the key points of the updated melanoma guidelines.
Cutaneous melanoma
Professor Chen Jing
Neoadjuvant therapy
The new "PD-1 inhibitor" is recommended for neoadjuvant treatment of cutaneous melanoma.
Reasons for Updating and Sources of Evidence:
The SWOG S1801 study is a randomized phase II study evaluating pembrolizumab for neoadjuvant and adjuvant therapy in patients with resectable stage III.B to IV melanoma, and is the first randomized controlled study in which the immune neoadjuvant + surgery + adjuvant "sandwich" treatment model challenges traditional postoperative adjuvant therapy. From February 2019 to May 2022, 154 patients aged 18 years and older with resectable melanoma (N=313) with stage III.B-III.D and stage IV (M1a, M1b, Mc) were enrolled in the study according to the RECIST criteria, 154 patients in the neoadjuvant group (3 cycles of pembrolizumab + surgery + 15 cycles of pembrolizumab), and 159 patients in the adjuvant group alone (surgery + 18 cycles of pembrolizumab).
The results showed that the 2-year event-free survival (EFS) rate was 72% in the neoadjuvant group and 49% in the adjuvant therapy alone group (HR 0.58, 95% Cl 0.39-0.87; P=0.004). The complete response (CR) and partial response (PR) rates were 6% and 41%, respectively, in the neoadjuvant group. EFS subgroup analysis showed a preference for neoadjuvant therapy for all stratification factors. This study is the first to demonstrate that moving immunotherapy forward to preoperative therapy can further improve patient outcomes compared to the current standard of care modality for resectable stage II and IV melanoma.
Adjuvant therapy
Among the grade III recommendations for adjuvant treatment of cutaneous melanoma, the recommendations of "nivolumab" and "ipilimumab" were deleted.
Late-stage treatment
Advanced first-line treatment: In the grade III recommendation for the first-line treatment of metastatic or unresectable stage III or IV cutaneous melanoma, delete "nivolumab".
Advanced second-line therapy: In the third-line recommendation for metastatic or unresectable stage III or IV cutaneous melanoma, "dabrafenib + trametinib + PD-1 monoclonal antibody for patients with BRAF V600 mutation" is added to the third-line recommendation for second-line treatment.
Reasons for Updating and Sources of Evidence:
In a meta-analysis of three large international randomized controlled trials (KEYNOTE-022, IMspire-150, and COMBI-I studies) investigating target-immune combinations in BRAF V600-mutant unresectable or metastatic melanoma, the target-immune combination compared with targeted therapy alone was associated with a significant advantage in progression-free survival (PFS) and overall survival (OS): a significant 23% reduction in the risk of progression (SHR=0.77) , the risk of death was significantly reduced by 21% (SHR=0.79). Subgroup analyses showed no effect on PFS by age, sex, ECOG score, lactate dehydrogenase (LDH), and PD-L1 levels.
Advanced treatment of acral melanoma
Professor Mao Lili
Moving the level of evidence forward: PD-1 monoclonal antibody + apatinib + temozolomide (acral, first-line treatment, level II recommendation)
Sources of evidence:
The CAP-03 study is a single-center, open-label, Phase II clinical study to evaluate the efficacy and safety of camrelizumab + apatinib + temomide in combination with first-line treatment of advanced acral melanoma. In this study, patients aged 18-75 years, histologically confirmed recurrent, unresectable or metastatic acral melanoma (stage III/IV), no prior history of systemic therapy, ECOG 0-1 and life expectancy of more than 12 weeks (N=48), were treated with camrelizumab 200mg q2W iv + apatinib 250mg qd po + temositamide 200mg/m2 on days 1-5 iv. The primary endpoint was objective response rate (ORR), and the secondary endpoints were PFS, disease control rate (DCR), OS, and safety.
The results of the study showed that 33 patients had tumor size regression of more than 30%, and 11 patients (22.9%) achieved PR on the first imaging evaluation. In terms of efficacy, the ORR was 66.7% (95% CI 51.6-79.6), the DCR was 91.7% (95% CI 80.0-97.7), the median PFS was 18.4 (95% CI 10.6-not reached) in the intention-to-treat (ITT) population, and the median OS results will be presented at ASCO. Compared with patients with high LDH expression and stable disease (SD), patients with low LDH expression and PR had more significant benefits in PFS and OS (P<0.05). The combination of camrelizumab + apatinib + temomide showed positive anti-tumor activity and a manageable safety profile.
Moving the level of evidence forward: lormatinib recommended if harboring NRAS mutations (acral, second-line therapy, level I recommendation)
Sources of evidence:
Results from the pivotal Phase II registration study of tolametinib in patients with advanced NRAS-mutant melanoma showed an ORR of 34.7% (95% CI 25.3-45.2;D), a CR of 72.6% (95% CI 62.5-81.3), a median duration of response (DOR) of 5.6 months (95% CI 2.9-8.3), and a median PFS of 4.2 months (95% CI 3.5-5.6). There were no treatment-related adverse events leading to death in terms of safety.
New: Advanced melanoma with tumor-infiltrating lymphocytes (TILs) that have failed multiple lines of therapy
Sources of evidence:
The C-144-01 study is a Phase II multicenter clinical study evaluating cryopreserved autologous tumor invasive lymphocyte therapy (Lifileucel) in the treatment of metastatic melanoma. The ORR of 153 patients with advanced melanoma (excluding uveal melanoma only) who underwent multiple lines of therapy was 31.4%. Twelve of these patients with mucosal melanoma achieved an ORR of 50%, and Lifileucel demonstrated clinically significant anti-tumor activity and durable responses.
Adjuvant therapy for mucosal melanoma
Professor Chen Yu
For resectable mucosal melanoma, perioperative adjuvant therapy is of great significance in reducing the risk of disease recurrence.
Multiple studies have confirmed that in reducing the risk of metastasis and recurrence: chemotherapy > high-dose interferon (HDI)
An open-label, multicenter, phase II randomized controlled study demonstrated the observation of chemotherapy (TMA+DDP) > HDI> in terms of recurrence-free survival (RFS) & OS (mRFS: 20.8 m vs 9.4 m vs 5.4 m, mOS: 48.7 m vs 40.4 m vs 21.2 m). Another phase III randomized controlled study reaffirmed that adjuvant chemotherapy (TMZ+DDP) significantly reduced the risk of recurrence and metastasis compared with HDI in the adjuvant treatment of mucosal melanoma (RFS: 15.53 vs 9.47, DMFS: 16.8 vs. 9.57, OS: 41.20 vs 35.73).
Head-to-head studies of PD-1 and HDI in mucosal melanoma showed that PD-1 had a superior safety profile over HDI and that RFS benefited longer in the PD-L1(+) subgroup.
The results of the study of temozolomide plus cisplatin versus toripalimab (anti-PD-1 monoclonal antibody) in the adjuvant treatment of resected mucosal melanoma suggest that adjuvant chemotherapy (temozolomide + cisplatin) is significantly more effective than toripalimab:
- RFS：28.2 vs 12.0个月，HR=0.64(0.42-0.98),P=0.04
- DMFS：42.0 vs 19.0个月，HR=0.58(0.36-0.92),P=0.02
- OS：93.4 vs 39.3个月，HR=0.56(0.33-0.94),P=0.03
- PD-1组PD-L1(+)患者表现出较好的RFS和DMFS，与化疗组更接近
- Adjuvant chemotherapy remains a good option for patients with resected mucosal melanoma
In terms of neoadjuvant therapy, toripalimab in combination with axitinib is a promising regimen.
According to the results of a phase II clinical study of toripalimab combined with axitinib for the neoadjuvant treatment of patients with resectable mucosal melanoma conducted by the team of Professor Guo Jun from Peking University Cancer Hospital, the pathological response rate of toripalimab combined with axitinib in the neoadjuvant treatment of patients with resectable mucosal melanoma was as high as 33.3%, and the median RFS of patients with pathological response was 11.7 months.
审校:Faline
Typesetting: KIKI
Execution: Uni
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