TMB標誌物顯神威！可增加小細胞肺癌I-O治療有效性 腫瘤資訊2018-05-15 編譯：月下荷花 來源：腫瘤資訊 CheckMate032研究表明，小細胞肺癌（SCLC）可獲益於免疫檢查點抑制治療，但哪些患者在免疫治療中獲益更多並不清楚。近日美國Hellmann教授在Cancer Cell雜誌發表了CheckMate032的回顧性研究，結果表明高腫瘤突變負荷(TMB)SCLC患者從納武利尤單抗（nivolumab）聯合伊匹木單抗（ipilimumab）治療中獲益最大。
研究背景 小細胞肺癌占所有肺癌10%–15%，大約75%患者為廣泛期。標準一線治療為含鉑化療，一旦疾病進展則缺少有效治療，預後極差。納武利尤單抗為免疫檢查點抑制劑，無論是單藥還是與伊匹木單抗聯合治療既往接受過治療的SCLC，均可獲得持續治療反應，延長生存。CheckMate 032研究中，納武利尤單抗單藥治療進展期SCLC的2年生存率14%，與伊匹木單抗聯合為26%，因此NCCN指南推薦納武利尤單抗±伊匹木單抗作為SCLC的二線或二線以上治療。然而一直缺少有效預測SCLC免疫檢查點抑制治療有效性的標誌。與其它腫瘤不同，SCLC較少表達程式化死亡配體1（PD-L1），而且無論有無PD-L1表達，納武利尤單抗±伊匹木單抗治療均可能有效。多數SCLC與吸煙有關，因此SCLC特徵之一是高體突變負荷。其它實體腫瘤中已顯示高TMB與免疫檢查點抑制治療有效性相關，但在SCLC中是否也存在這種關係並不清楚。
研究方法CheckMate032研究中接受納武利尤單抗單藥（3mg/kg，每2週一次）或納武利尤單抗+伊匹木單抗（1mg/kg+3mg/kg，每3週一次，共4週期，然後納武利尤單抗3mg/kg，每2週一次）聯合治療的SCLC患者進行全外顯子測序。TMB定義為錯義體突變總和，採用三分位法將TMB分為低負荷＜143突變，中等負荷143-247突變，高負荷≥248突變。
研究結果 結果表明納武利尤單抗單藥和納武利尤單抗+伊匹木單抗聯合治療，高TMB患者的客觀反應率（21.3%和46.2%）高於低（4.8%和22.2%）和中（6.8%和16.0%）TMB患者，所有患者納武利尤單抗+伊匹木單抗聯合治療的客觀反應率高於納武利尤單抗單藥治療。無論是聯合還是單藥治療，獲得完全或部分反應患者的TMB高於疾病穩定或疾病進展的患者。納武利尤單抗單藥和納武利尤單抗+伊匹木單抗聯合治療，高TMB患者的1年無進展生存率（21.2%和30.0%）高於低（不能計算和6.2%）中（3.1%和8.0%）腫瘤突變患者，高TMB患者聯合治療的1年無進展生存率優於單藥治療，低中TMB患者聯合治療與單藥治療無差異，總生存結果與之相似。總之，高TMB增迦納武利尤單抗和納武利尤單抗+伊匹木單抗有效性，納武利尤單抗+伊匹木單抗的臨床獲益超過納武利尤單抗單藥。
結果討論與展望這項研究評估了SCLC的TMB與免疫檢查點抑制治療有效性的關係，結果表明高TMB 患者較低中TMB患者從納武利尤單抗和納武利尤單抗+伊匹木單抗治療中獲益更多，這與納武利尤單抗治療非小細胞肺癌（NSCLC）和尿路上皮癌、伊匹木單抗治療黑色素瘤的結果相似，因此TMB可能也是SCLC免疫檢查點治療反應的預測標誌。初始觀察發現雖然納武利尤單抗+伊匹木單抗聯合治療SCLC能增加獲益，但較納武利尤單抗單藥治療的毒性更大，因此確定單藥或聯合治療的不同預測標誌十分必要。這項研究發現，SCLC患者伴高TMB時，納武利尤單抗+伊匹木單抗聯合治療的生存遠超過歷史對照，中低TMB患者聯合治療的客觀反應率雖較單藥改善，但無進展生存和總生存並無差別。結果提示高TMB患者，聯合治療獲益優於單藥治療，而中低TMB患者單藥治療也許是最佳選擇。這項研究表明，TMB對SCLC免疫治療反應有預測作用，但尚不清楚其分子多樣性是否足以區分免疫治療反應不同的臨床亞組，目前只能得出負荷最高者免疫治療獲益最多。有人認為突變負荷分析並不可行，因為SCLC標本取材多為小標本且存在較多壞死組織。但這項研究顯示，61%患者的活檢組織足以用於全外顯子檢測，因為是回顧性研究，活檢取材時並未預先計畫全外顯子檢測，若事先計畫全外顯子檢查則取材合乎標準的患者比例可能更高。總之這項研究證實，SCLCTMB檢測可行，如若為前瞻性研究則可獲更高的成功率。目前不清楚TMB和納武利尤單抗+伊匹木單抗治療結果之間究竟如何產生聯繫。有假說認為，加入伊匹木單抗增加抗腫瘤T細胞克隆儲備，同時也降低TMB的預測相關性。但這個假說似乎與SCLC無關，因為TMB在SCLC中是納武利尤單抗+伊匹木單抗治療反應增加的預測標誌。與之相似，有研究顯示NSCLC採用納武利尤單抗+伊匹木單抗聯合治療的反應進一步改善。需要更多研究明確二者協同作用的潛在免疫學機制。研究還發現，不論是均分法、三分法還是四分法，皆顯示高TMB與結果改善相關，說明SCLC的TMB與免疫治療獲益的關係很穩定，同時也提示多個閾值均可富集獲益人群，需要進一步優化，也要更好地理解增加免疫原性的體突變分子特徵。目前另有二個評估納武利尤單抗±伊匹木單抗治療SCLC有效性的III期研究（CheckMate331和CheckMate451），這二項研究會有更多資料明確TMB與治療結果間的關係。總之，SCLC患者採用納武利尤單抗單藥或納武利尤單抗+伊匹木單抗聯合治療時，高TMB能增加治療有效性，其中以聯合治療的臨床獲益更多，聯合治療的1年生存率幾乎是單藥治療的2倍。高TMBSCLC患者接受免疫聯合治療時，無進展生存和總生存改善尤其顯著，這與NSCLC的資料相似，提示TMB可能是所有肺癌免疫治療的潛在生物學標誌。
Tumor Mutational Burden and Response Rate to PD-1 Inhibition
December 21, 2017 N Engl J Med 2017; 377:2500-2501
TO THE EDITOR: Inhibitors of programmed death 1 (PD-1) protein or its ligand (PD-L1) have shown remarkable clinical benefit in many cancers.1 One emerging biomarker of response to anti–PD-1 therapy is the tumor mutational burden (i.e., the total number of mutations per coding area of a tumor genome). This finding is supported by the clinical activity of anti–PD-1 therapy in colorectal cancer with mismatch repair deficiency, a tumor subtype with a high tumor mutational burden, as compared with the colorectal cancer subtype with mismatch repair proficiency, which has a significantly lower tumor mutational burden and a poor response to these agents.2,3
To evaluate the relationship between the tumor mutational burden and the objective response rate, we plotted the objective response rate for anti–PD-1 or anti–PD-L1 therapy against the corresponding median tumor mutational burden across multiple cancer types (Figure 1). Through an extensive literature search, we identified 27 tumor types or subtypes for which data regarding the objective response rate are available. For each tumor type, we pooled the response data from the largest published studies that evaluated the objective response rate. We included only studies of anti–PD-1 or anti–PD-L1 monotherapy that enrolled at least 10 patients who were not selected for PD-L1 tumor expression. (Details about the methods are provided in the Supplementary Appendix, available with the full text of this letter at NEJM.org.) The median tumor mutational burden for each tumor type was obtained from a validated comprehensive genomic profiling assay performed and provided by Foundation Medicine.4 We observed a significant correlation between the tumor mutational burden and the objective response rate (P<0.001). The correlation coefficient of 0.74 suggests that 55% of the differences in the objective response rate across cancer types may be explained by the tumor mutational burden. Some cancer subtypes have a response to therapy that is better than would be predicted by the tumor mutational burden (e.g., Merkel-cell carcinoma), and some have a response that is worse than would be predicted (e.g., colorectal cancer with mismatch repair proficiency). The higher-than-anticipated objective response rates for Merkel-cell carcinoma and some other cancers that have been associated with viruses suggest that the presentation of viral antigens on certain tumor types may confer an increased response rate to anti–PD-1 therapy.5
Our linear correlation formula — objective response rate=10.8×loge(X)−0.7, where "X" is the number of coding somatic mutations per megabase of DNA — can be used to make hypotheses with respect to the objective response rate in tumor types for which anti–PD-1 therapy has not been explored. For example, we anticipate a clinically meaningful objective response rate of 40.1% (95% confidence interval [CI], 31.2 to 50.6) for basal-cell carcinoma of the skin and of 20.6% (95% CI, 16.7 to 24.5) for sarcomatoid carcinoma of the lung on the basis of a median tumor mutational burden of 47.3 and 7.2, respectively.4 We anticipate a low objective response rate (<5%) for several other cancers (e.g., pilocytic astrocytoma and small-intestine carcinoid).4 A limitation of our analysis is that the sequenced tumor specimens were probably not the same ones for which clinical responses were assessed. Many different factors modulate the clinical response to an immune checkpoint inhibitor, but our findings highlight the strong relationship between the tumor mutational burden and the activity of anti–PD-1 therapies across multiple cancers.Mark Yarchoan, M.D. Alexander Hopkins, Ph.D. Elizabeth M. Jaffee, M.D. Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD ejaffee@jhmi.edu
Correlation between Tumor Mutational Burden and Objective Response Rate with Anti–PD-1 or Anti–PD-L1 Therapy in 27 Tumor Types.
