The New England Journal of Medicine published a document on September 2nd, pointing out that after one year of dual-target postoperative adjuvant therapy, it can not only delay the recurrence, but also increase the proportion of patients without recurrence for a long time. After five years' follow-up, the median recurrence-free survival (RFS) was not reached, and half of the patients had no recurrence and no long-term side effects. COMBI-AD study proved the efficacy and safety of darafenib combined with trimetinib in adjuvant treatment of stage III resectable melanoma with BRAF V600E or V600K mutation.
Research background:
For high-risk resectable melanoma patients at home and abroad, darafenib combined with trimetinib is the standard postoperative adjuvant therapy. In order to verify the long-term recurrence-free survival of melanoma patients brought by 1 year dual-target adjuvant therapy, COMBI-AD study analyzed the 5-year follow-up data.
Research methods:
COMBI-AD study randomly divided 870 patients with stage Ⅲ BRAF V600E or V600K mutant melanoma who had been surgically removed into two-target treatment group and control group. The treatment group (438 cases) received 1 year oral darafenib (150mg, twice a day) combined with trimetinib (2mg, once a day/kloc-0). The primary end point is recurrence-free survival (RFS), and the specific research design is shown in figure 1. The median follow-up time of darafenib combined with trimetinib was 60 months, and the last patient received the last dose of double target or placebo in February 2065438+2005.
Figure 1. Research and design of combined advertising
Research results:
The results of evaluating RFS in ITT population are shown in Figure 2. The 5-year RFS rate of darafenib combined with trimetinib was 52%(95%CI, 48%-58%), while that of placebo group was 36%(95%CI, 32%-4 1%). Combining 3-year and 4-year RFS interest rates, it shows advantages. In terms of median RF, the double-target treatment group has not reached NR (95% CI, 47.9 to NR), while the placebo group is 16.6 months (95% CI, 12.7 to 22. 1). Compared with placebo, the double-target treatment group can reduce the risk of recurrence or death by 49% (hazard ratio is 0. In addition, in all subgroups, the dual-target treatment group showed the benefits of RFS (see Figure 3).
Figure 2. Evaluation of RFS results in ITT population
Figure 3. Forest map of recurrence or death risk ratio in different subgroups.
Research conclusions:
In the five-year analysis of COMBI-AD, a phase III clinical study, for melanoma patients whose BRAF V600E or V600K mutation has been removed, 65,438+0 years of darafenib combined with trimetinib as adjuvant therapy brought long-term recurrence-free survival, lasting distant metastasis and no obvious long-term toxic and side effects. ?
Professor Lu Si commented:
Commentators
Chief physician Lu Si, doctoral supervisor.
Chief physician of Peking University Cancer Hospital
Author of CSCO guidelines for diagnosis and treatment of melanoma.
Author of "Guidelines for Toxicity Management of Inhibitors at CSCO Immune Checkpoints"
Vice chairman of CSCO melanoma expert Committee
Vice chairman of CSCO neurological oncology Committee
Vice Chairman of the Special Committee of Brain Metastasis of Beijing Medical Award Foundation
Standing Committee of CSCO Rare Tumor Professional Committee
Standing Committee of CSCO Committee of Young Experts
Standing Committee of CSCO patient education expert Committee
Member of CSCO immunotherapy committee, deputy editor-in-chief of young editorial board of Journal of Oncology, peer reviewer of Clinical Oncology Research.
Mainly engaged in clinical and translational medicine research of melanoma and urinary system tumors. More than 40 papers have been published, and the first author or correspondent has published more than 20 SCI papers, with a total impact factor of nearly 200 points and the highest citation times of a single article of 372 times. At the International Melanoma Conference, more than 65,438+00 papers were published in the form of conference reports and wall newspapers. Participated in three books. Presided over 6 national and provincial and ministerial funds. Won 4 provincial and ministerial scientific and technological progress awards. National Cancer Center won the special prize of 1 research paper.
Expert review
First of all, NEJM released a five-year analysis of dual-target adjuvant therapy, which has significant long-term benefits and good safety.
The recurrence risk of high-risk melanoma with stage IIB and above is higher, and patients with BRAF mutation may have higher recurrence risk and worse prognosis than those with wild BRAF. Standardized adjuvant therapy is expected to improve this situation, and the long-term benefit and safety of treatment are crucial.
1.COMBI-AD has been studied for 5 years, and the long-term benefits are remarkable.
From the five-year analysis of COMBI-AD (the longest follow-up of targeted adjuvant therapy so far), after one year of adjuvant therapy with darafenib and trimetinib and a median follow-up of 60 months, the median RFS has not yet been reached, and the benefits have entered a plateau from the RFS rate of 3 years, 4 years and 5 years. Previous studies have shown that the recurrence of stage III melanoma mostly occurs in the first three years after operation. COMBI-AD research shows that dual-target therapy can not only delay recurrence, but also increase the percentage of long-term relapse-free patients, and the results are very exciting.
The number of OS events of COMBI-AD research did not reach the preset value and was not published. We saw that Weibull mixed cure rate model was used in the study. The model analyzes the long-term survival rate by evaluating the recurrence-free survival rate, which is not affected by post-discharge treatment. As early as 20 18, the model analysis results predicted that the possible cure rate of double targets was 54%. We will always pay attention to the overall survival results of dual-target adjuvant therapy reported in the future.
2. Compi-AD has studied safety analysis for 5 years, which is easy to manage and control.
There is no latest safety analysis in the results published in the New England Journal, because no patients continue to receive dual-target treatment during the follow-up period, and most of the dual-target adverse reactions occur in the first year of treatment, and almost all the dual-target adverse reactions are short-lived and can be solved by stopping the drug. We still need to explore the standardized management of adverse reactions of dual-target therapy for China patients.
Second, the thinking and future prospect brought by the research.
1. Can the real world replicate the results of clinical research?
At present, several international studies on adjuvant therapy of melanoma, including COMBI-AD, CheckMate238 and KEYNOTE-054, are based on the completion of lymph node dissection. However, according to the latest research results of MSLT-II and DeCOG, patients with positive sentinel lymph nodes can consider immediate lymph node dissection or close monitoring of regional lymph nodes. For China patients with deep infiltration and high ulcer rate, it is still controversial whether sentinel lymph node dissection can be abandoned. At present, there is no data to analyze the benefit difference of adjuvant therapy between patients with lymph node dissection or not. It is difficult to judge whether the real world can repeat the results of several international adjuvant therapy studies, and more clinical practice is needed to explore the standardized path of adjuvant therapy in China.
2. Is the plateau in the placebo group caused by the influence of follow-up treatment?
After five years of follow-up, we can see that both the double-target treatment group and the placebo control group have a plateau period, and the proportion of the double-target treatment group receiving treatment after leaving the group is obviously lower than that of the placebo control group, but even so, the proportion of the treatment group and the placebo group receiving follow-up immunotherapy (including double immunization combined with anti-PD- 1+ anti-CTLA-4) is close to 26% and 28% respectively, so the follow-up immunotherapy is helpful to promote the plateau period. In a word, reasonable deployment of different adjuvant therapies can bring more benefits to melanoma patients in China.
3. The benefits of different subgroups are different.
We pay close attention to the RFS analysis results of different subgroups. All subgroups of patients receiving dual-target therapy showed the benefits of RFS treatment. Based on AJCC-7, the double-target therapy in different subgroups has a longer recurrence-free survival time than that in placebo group, and the risk ratio of recurrence or death is lower than that in iiic >: IIIB & gtIIIA, it seems that the later the staging, the more obvious the benefits.
Third, summary.
Based on the results of COMBI-AD research, darafenib combined with trimetinib has become the first therapy in China for adjuvant treatment of BRAF V600 mutant melanoma, and it was written into the Class I recommendation for adjuvant treatment of skin melanoma in CSCO guidelines in 2020. It is expected that dual-target adjuvant therapy will bring more hope to more patients with stage III BRAF mutation.