從BRAF V600E腸癌的精準治療看中美癌症臨床治療之間的差距
從BRAF V600E腸癌的精準治療看中美癌症臨床治療之間的差距
來自專欄基於基因組學診斷的癌症靶向治療
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今天接到一個腸癌患者的求助，測序後發現BRAF V600E/TP53 R175H/PIK3CA H1047R是主要的驅動突變。 她在國內排名前十的一家醫院就診，主治醫生按照CSCO 2018指南選用了聯合化療方案, 效果不佳，7個月之後諮詢美國專家改用NCCN 2018的靶向治療方案，目前病情得到控制。我之前寫過MSKCC的精準腸癌靶向治療， 三種治療方案在方法學上存在顯著的代差， 所以我決定寫篇文章分析一下。
中美癌症臨床治療方法學上的時間差異有六種情況：第一級， 中國的CSCO, 第二級， 美國的NCCN, 第三級， FDA批准，但是NCCN還沒有納入； 第四級， FDA還沒有批准，但是臨床試驗結果有效並已經發表； 第五級，臨床試驗結果有效， 還沒有在學術期刊上發表，但是已經在ASCO級別的會議上公布； 第六級， 臨床試驗有效，但是還沒有在會議上公開，但是圈子裡的人已經知道了。
先給出2016年的ASCO會議報告作為參考文獻如下：
Understanding BRAF-Mutant Colorectal Cancer
A recent trial by Loupakis et al. has shown promising outcomes for patients withBRAF-mutated tumors treated with a highly aggressive chemotherapy regimen (i.e., FOLFOXIRI plus bevacizumab). In this trial, patients with metastatic CRC who received FOLFOXIRI plus bevacizumab achieved progression-free survival that was approximately 2.5 months longer than in those who were treated with FOLFIRI. Unfortunately, even with this regimen, survival for patients withBRAFMutCRC was still less than half that of patients with wild-type tumors (median overall survival, 19.0 months vs. 41.7 months).
簡而言之，常規化療方案效果並不是很好，附帶說一下，中國2018 CSCO對於轉移腸癌的治療方案的依據是下面這篇2014年的新英格蘭醫學雜誌文章。
醫生選擇的就是稍好一點的FOLOXRI+bevacizumab方案。
很多情況下，2014年的新英格蘭醫學雜誌文章已經不錯了，但是對於BRAF突變的腸癌，這個領域進展非常快，2016年的 ASCO大會上，上面這個方案就已經過時了，
The relative lack of durable response to standard cytotoxic agents, along with the successes found in treating BRAFMut melanoma, has led to a multitude of studies designed to exploit BRAF as an important driver mutation. One of the first of these trials, which used single-agent vemurafenib (a selective BRAF V600E inhibitor) in 21 patients with BRAFMut CRCs, yielded surprisingly poor results. Only one patient achieved a partial response, which equated to an overall response rate of approximately 5% compared with single-agent response rates for the same drug used in melanoma, for which overall response rates are generally closer to 60% or 75%.
先說化療效果不好，然後使用單一BRAF V600E抑製劑vemurafenib治療腸癌效果也不好， 所以大家開始聯合靶向治療的嘗試， 介紹了多個針對BRAF靶向治療的臨床試驗。
A few new trials combining BRAF and EGFR inhibition with a third agent for patients with metastatic BRAFMut CRC are worth noting. The first combines the MEK inhibitor trametinib with dabrafenib and panitumumab. As of the latest update, nine (26%) of 35 patients who received the triplet regimen have achieved at least a partial response.24The second of these triple-agent trials combines theBRAF and EGFR inhibitors encorafenib and cetuximab with the a-specific PI3K inhibitor alpelisib. The latest update from this trial, given at the 2014 European Society for Medical Oncology Annual Meeting, showed that nine (32%) of 28 patients who received triple therapy achieved at least a partial response. The last of these triple-agent trials combined theBRAF and EGFR inhibitors vemurafenib and cetuximab with irinotecan. At last update, 17 patients with metastatic BRAFMut CRC were evaluable for response, of which six (35%) had achieved at least a partial response.
2016年的ASCO會議特別關注了三葯聯用的試驗(trametinib, dabrafenib and panitumumab)。
這裡我不糾纏，直接跳到2018 NCCN colon cancer.
NCCN Guidelines Insights: Colon Cancer, Version 2.2018BRAF is downstream of EGFR and RAS in the MAPK signaling pathway. The BRAFV600E mutation results in constitutive MAPK signaling that encourages cellular proliferation.37 Vemurafenib selectively inhibits the V600E-mutated form of the BRAF kinase, thereby reducing aberrant MAPK signaling.38 It has an FDA indication for treatment of patients with BRAF V600E–mutated, unresectable, or metastatic melanoma.39 However, vemurafenib monotherapy has shown limited activity in mCRC.40 Preclinical data suggest that BRAF V600E inhibition alone is ineffective because feedback activation of EGFR occurs.41,42 Therefore, blockage of EGFR and BRAF V600E together has been speculated to be more effective than BRAF V600E inhibition alone. In fact, preclinical studies show a synergistic effect of such dual inhibition.41,42 However, vemurafenib in combination with cetuximab- or panitumumab-based therapy has been ineffective in early clinical trials.43 Results from preclinical and early clinical studies suggest that the addition of irinotecan to BRAF and EGFR inhibition may improve antitumor activity.44,45
The combination of vemurafenib, cetuximab, and irinotecan was thus tested in patients with BRAF V600E–mutated mCRC in the recent phase II SWOG S1406 trial. In this trial, 99 patients with BRAF-mutant, RAS wild-type tumors who received 1 or 2 prior regimens were randomized to irinotecan and cetuximab with or without vemurafenib.9 The NCCN Panel reviewed updated results of this trial that were presented at the 2017 ASCO annual meeting. The primary end point of median progression-free survival (PFS) was improved in the vemurafenib arm (4.3 vs 2.0 months; HR, 0.48; 95% CI, 0.31–0.75; P=.001). Response was also improved, with response rates (only partial responses [PRs] were seen) of 4% vs 16% (P=.08) and disease control rates (partial responses + stable disease) of 22% vs 67% (P=.001). Grade 3/4 adverse events (AEs) that were higher in the vemurafenib arm included neutropenia (33% vs 7%), anemia (13% vs 0%), and nausea (20% vs 2%). Crossover was allowed for the cetuximab/irinotecan group, and 48% of those patients received vemurafenib at time of progression. Of those who crossed over, the partial response rate was 17% and the stable disease rate was 55%, for a disease control rate of 72%. The HR for the secondary end point of OS, which would be attenuated by the crossover, was 0.73 (95% CI, 0.45–1.17; P=.19).
美國教授推薦的方案就是按照NCCN 2018的指南做出的三葯聯用vemurafenib, cetuximab, and irinotecan， 目前暫時控制住病人的病情進展。這就是我說的第二級的治療。和ASCO一樣，NCCN在下面留了一個三葯聯用的伏筆。
The panel noted that trametinib/dabrafenib/panitumumab is currently being studied in an open-label phase I/II trial of patients withBRAFV600E–mutated mCRC (ClinicalTrials.govidentifier:NCT01750918).
下面開始介紹第三級，也就是NCCN沒有納入，但是FDA已經批准的治療方案， 目前在MSKCC使用, 臨床試驗的結果跟2018 NCCN同月發表，完美錯過。
Although BRAF inhibitor monotherapy yields response rates >50% in BRAF V600-
mutant melanoma, only approximately 5% of patients with BRAF V600E colorectal
cancer respond. Preclinical studies suggest that the lack of efficacy in BRAF V600E colorectal cancer is due to adaptive feedback reactivation of MAPK signaling, often mediated by EGFR. This clinical trial evaluated BRAF and EGFR inhibition with dabrafenib (D) + panitumumab (P) ± MEK inhibition with trametinib (T) to achieve greater MAPK suppression and improved efficacy in 142 patients with
BRAF V600E colorectal cancer. Confirmed response rates for D+P, D+T+P, and T+P were 10%, 21%, and 0%, respectively. Pharmacodynamic analysis of paired pretreatment and on-treatment biopsies found that efficacy of D+T+P correlated with increased MAPK suppression. Serial cell-free DNA analysis revealed additional correlates of response and emergence of KRAS and NRAS mutations on disease
progression. Thus, targeting adaptive feedback pathways in BRAFV600E colorectal cancer can improve efficacy, but MAPK reactivation remains an important primary and acquired resistance mechanism.
說白了，就是擁有BRAF V600E突變腸癌對單一BRAF V600E激酶抑製劑很快產生抗性，原因是癌細胞通過EGFR受體激酶途徑激活下游的MAPK激酶。
不用藥就是左邊，BRAF通過MEK刺激細胞生長增殖。單獨用BRAF抑製劑見中間，癌細胞通過EGFR/RAS/CRAF/MEK繞小路還是能刺激細胞生長增殖。只有右邊示意圖裡面的三葯聯用，同時抑制EGFR, BRAF, MEK， 靶向治療才能發揮最佳效果。
所以開展了臨床試驗看看什麼樣的組合治療效果最好，有兩組是使用兩個藥物，第三組是三葯聯用， 生存曲線見下圖：
兩葯聯用沒有病人生存期超過9個月，但是三葯聯用有病人生存期超過4年， ASCO特意報道了這個等待了3年多的BEACON臨床試驗。
Triplet Therapy Poses a Triple Threat to BRAF-Mutated Colorectal Cancers
今年8月FDA正式批准BRAF V600突變的腸癌在一線或二線靶向治療失敗以後，醫生可以使用這個新的治療方案， 這也是目前MSKCC使用的主要治療方案。
FDA Grants Breakthrough Therapy Designation for Encorafenib Plus Binimetinib and Cetuximab in我給病人的建議就是，如果現在使用的NCCN 2018方案失效，就使用最後這個還沒有納入NCCN的三葯聯合治療方案。
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