膽管癌的精準治療方略(UCSF 2018版）
如果你是醫生，能讀英文，直接看下面ASCO的官網文章即可：
Future Treatment of Cholangiocarcinoma
說起來這是一年前的事情了，ASCO採訪了UCSF的膽管癌臨床試驗負責醫生Robin Kate Kelley, 後者介紹了膽管癌精準治療的進展， 我個人覺得協和醫院和UCSF的膽管癌團隊相比應該有3年以上的差距。
Gemcitabine plus cisplatin (ABC-02) remains the standard first-line systemic therapy for advanced cholangiocarcinoma, although it leaves much to be desired, as median survival is less than 1 year. There are currently no established regimens for the second line and beyond. Prior molecular targeted therapies (predominantly epidermal growth factor receptor [EGFR] or vascular [VEGFR]) in unselected populations of patients with cholangiocarcinoma have not shown a benefit, and no studies have been enriched for a target-positive population.
一線化療中位生存期不到1年，沒有標準的2線治療方案， EGFR/VEGFR的靶向治療臨床試驗宣告失敗，這就是訪談的大背景。
Genetic Heterogeneity
WHOLE-GENOME and epigenomic analysis on 489 tumors, performed by the International Cancer Genome Consortium, has revealed the genetic heterogeneity of cholangiocarcinomas.2 Four distinct genetic clusters were identified, defined by mutation and copy number profiles, gene expression, and epigenetics.
For example, cluster 1 was enriched in TP53, ARID1A, BRCA1/2 mutations, and HER2 amplification. Cluster 2 was enriched with TP53 mutations. Both clusters occurred equally as extrahepatic and intrahepatic tumors and were liver fluke-positive or fluke-negative. Cluster 4 was enriched in BAP1 and IDH1/2 mutations as well as fibroblast growth factor receptor (FGFR) alterations and was predominantly intrahepatic and fluke-negative, as was cluster 3.
「The prognosis was distinct, and it was best for cluster 4,」 she noted. In the International Cancer Genome Consortium study, approximately 60% of patients in cluster 4 were alive at 7 years, compared with 0% to 40% of patients in the other clusters (P < .0001). 「Molecular stratification will gradually replace anatomic as we learn more about the prognostic value and natural history of some of these molecularly defined cohorts,」 she said.
膽管癌讓人頭疼的原因就是背後遺傳學發病機制的多樣性，這是通過大規模測序才得知的結果。
相關的背景知識我已經寫文章介紹過，沒讀過的參考下面的鏈接：
殺生丸：膽管癌的精準靶向治療
FGFR2 Inhibitors
THE BETTER PROGNOSIS for cluster 4 may be partly due to its enriched presence of FGFR2 fusion, as they have been associated with improved outcomes. FGFR fusions, which are present in about 15% of intrahepatic tumors, are driver events that result in ligand-independent activation of the FGFR pathway.
An orally available, selective, ATP-competitive pan-FGFR inhibitor has shown activity in tumor models with FGFR alterations. This led to a phase II trial of BGJ398 in 61 heavily pretreated patients with FGFR alterations (79% had FGFR fusions).3 The response rate was 19% overall, rising to 23% in patients with fusions (those with other FGFR alterations did not benefit). Some degree of tumor regression was seen in the majority of patients, Dr. Kelley reported.
Median progression-free survival was 6.7 months, which 「compares very favorably to second-line cytotoxic fluorouracil-based therapy, which is generally about 3 months in retrospective studies,」 she noted. 「We (at UCSF) had, for example, a patient with multifocal intrahepatic tumors and nodal metastases who showed a dramatic partial response, which was sustained for almost 9 months, along with other patients with even longer responses in the trial.」
In an impressive case series, Goyal et al reported that polyclonal secondary FGFR2 kinase domain point mutations arise in the setting of acquired resistance to BGJ398. Some of these mutated tumors may be susceptible to structurally different FGFR2 inhibitors in preclinical studies, she said.
One of these agents is TAS-120, a highly selective, covalent pan-FGFR inhibitor that has shown activity against FGFR2 resistance mutations. In a phase I/II basket trial of 23 patients with FGFR2 fusion and other FGFR-altered cholangiocarcinomas, 4 of 9 patients with FGFR2 fusions achieved at least an unconfirmed partial response, and 8 patients had tumor regression.4 Other alterations were generally not as responsive. TAS-120 is currently being evaluated in a large basket trial with planned enrollment of over 800 patients.
「Multiple FGFR2-targeted agents are poised for pivotal trials in the first line and beyond, for advanced cholangiocarcinoma,」 she said.
這裡出現第一個要點，就是針對FGFR2的靶向治療，協和使用的樂伐替尼就是這個思路， 相關文章我也寫過：
殺生丸：閑談協和醫院使用樂伐替尼聯和PD1抗體治療KRAS G12驅動的膽管癌為什麼無效用藥需要對症， KRAS驅動的膽管癌使用樂伐替尼就不會有效，這也是協和的敗筆。我更關注的是更加專一的FGFR2抑製劑BGJ398和TAS-120, 這兩個葯有望比樂伐替尼取得更好的療效。
IDH1 Inhibitors
ANOTHER PROMISING target is the isocitrate dehydrogenase-1 (IDH1) mutation, which occurs in about 20% of intrahepatic tumors. This mutation results from the accumulation of oncometabolite 2-hydroxyglutarate, which blocks differentiation and leads to uncontrolled proliferation of de-differentiated tumor cells.
Ivosidenib (AG-120), a first-in-class oral, selective, reversible inhibitor of mutant IDH1, is currently in phase III trials of cholangiocarcinoma and acute myelogenous leukemia. In a phase I study of 73 heavily pretreated patients with cholangiocarcinoma, ivosidenib was well tolerated and produced responses in 5% of patients as well as stable disease in 56%; median progression-free survival was 3.8 months, and 12-month progression-free survival was 20.7%.5 Treatment with ivosidenib seems to restore cholangiolar differentiation of cells that are undifferentiated at baseline, based upon paired biopsy findings in a subset of patients enrolled in this study.
The phase III ClarIDHy trial is currently assessing ivosidenib as second- or third-line treatment in 186 patients; this is the first integral biomarker-selected phase III trial in this tumor type. 「The results of ClarIDHy will determine the efficacy of ivosidenib as monotherapy in this population. Its favorable safety profile suggests we can use it in combination,」 she said.
BAY1436032 is another mutant IDH1-targeted small molecule now in a phase I basket trial of 100 patients. In addition, olaparib (Lynparza) is being evaluated in a phase II trial of 75 patients based on the provocative finding that the mutant IDH1 oncometabolite may suppress homologous recombination in preclinical models.
IDH1/2基因突變驅動的膽管癌病人需要使用IDH1/2抑製劑進行治療，美國FDA已經批准，中國還沒有批准入市，這就給中國的膽管癌病人挖了一個坑，合法的藥物無效，有效的藥物不合法。
Targeting Mismatch Repair
AS WITH OTHER gastrointestinal cancers, about 2.5% of cholangiocarcinomas have mismatch repair (MMR) deficiency, which makes them a target for programmed cell death protein 1 (PD-1) inhibitors. In small subsets of cholangiocarcinoma in two KEYNOTE trials, outcomes of treatment with pembrolizumab (Keytruda) were positive.
Among 86 patients in KEYNOTE-016 with mismatch repair– deficient tumors, 4 patients had cholangiocarcinoma; the overall response rate was 53%, with 21% being complete responses; 2-year overall survival was 64%.6 Among 94 patients with mismatch repair–deficient tumors enrolled in KEYNOTE-158, there were 9 patients with cholangiocarcinoma; the overall response rate was 37%, and as of the latest report, the median duration of response had not been reached. Testing for MMR deficiency is now indicated in cholangiocarcinoma, Dr. Kelley said.
Whether pembrolizumab might also have value in MMR-proficient (microsatellite-stable) biliary cancers will also be determined in the KEYNOTE-158 basket trial. In this subgroup, other immunotherapy strategies or combinations may be needed, and these studies are underway.
DNA錯配修復缺陷的膽管癌病人適合使用PD1抗體，協和的1期臨床試驗也確認了這一點，但是對於不符合條件的膽管癌病人使用PD1抗體就沒有太大意義了。
Unselected Trials of Targeted Agents Plus Chemotherapy
ALTHOUGH MOST research is focused on biomarker-selected therapy, there is also a role for unselected trials, according to Dr. Kelley. This type of trial is appropriate when there are high rates of pathway activation and/or synergy with chemotherapy or resistance mechanisms at play.
Several ongoing randomized phase II trials are evaluating chemotherapy plus novel agents targeting EGFR, MEK, MET, VEGFR2, and other pathways. The 300-patient JSBF RP2 trial is studying the anti-VEGF agent ramucirumab (Cyramza) and the MET inhibitor merestinib plus gemcitabine and cisplatin in the first-line setting. Since EGFR activation is common in biliary tract cancer, the EGFR inhibitor varlitinib is being evaluated in combination with capecitabine, as second-line therapy, in the 120-patient phase II TreeTopp study, with plans to increase enrollment to 482 patients for the phase III trial.
靶向治療聯合化療的臨床試驗，這就要因人而異了。
基本上我給國內的膽管癌病人提供治療建議，就是按照UCSF的2018年膽管癌方略來進行的，首先測序，然後按照驅動突變推薦不同的治療方案， 現在你們就明白為什麼我看不上協和不管三七二十一就給並病人使用樂伐替尼聯合PD1抗體進行治療的原因了，這不是精準治療，這是粗放治療， 效果有限一點也不奇怪。
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