Recent progress and limitations of chemotherapy for pancreatic and biliary tract cancers

Gemcitabine chemotherapy has been the standard for advanced pancreatic cancer for more than a decade. New oral fluoropyrimidines such as S-1 and capecitabine are other key drugs. Gemcitabine plus erlotinib was the only combination therapy that significantly prolonged survival, although the effect was minimal. Little or no improvement in survival with recent molecular-targeted drugs might be attributed to the very high incidence of K-ras gene mutation in pancreatic cancer. Recently, the non-gemcitabine-based-regimen of FOLFIRINOX showed significantly greater overall survival compared with gemcitabine for the first time. For biliary tract cancer, gemcitabine plus cisplatin combination chemotherapy has been proved to significantly prolong survival and will become the standard therapy. Further improvement in survival is expected by the addition of cetuximab.     

Targeted therapies for treatment of non‐small cell lung cancer—Recent advances and future perspectives

Non‐small cell lung cancer (NSCLC) is one of the most deadly cancers worldwide, with poor prognosis once the disease has progressed past the point at which surgery is a viable option. Whilst chemotherapy has improved survival over recent decades, there is still great need for improvements in treatments for patients with advanced disease. Over the last decade, a variety of such drugs have received market approval for treating NSCLC, with a variety of others in the pipeline. Here, we review the development of targeted therapies for the treatment of advanced or metastatic NSCLC, including those already in clinical practice and those in early trials. The epidermal growth factor receptor (EGFR) inhibitors, gefitinib, erlotinib and afatinib; the anaplastic lymphoma kinase (ALK) inhibitor, crizotinib; and the anti‐vascular endothelial growth factor receptor monoclonal antibody, bevacizumab, are already providing improved survival for patients with NSCLC. Moreover, the discovery of EGFR mutations and ALK rearrangements has enabled the identification of patients who are more likely to benefit from a specific drug. The recent approval of the immune checkpoint inhibitor nivolumab, along with the designation of alectinib and MPDL3280A as breakthrough therapies by the FDA, demonstrates how rapidly this area of research is expanding. Over the last decade there has been significant progress made in the treatment of advanced NSCLC, and the large and varied selection of drugs currently undergoing trials provide great promise for improving the prognosis of this highly prevalent and deadly form of cancer.     

Future applications of FGF/FGFR inhibitors in cancer

Introduction: Deregulation of the fibroblast growth factor (FGF)/FGF receptor (FGFR) network occurs frequently in tumors due to gene amplification, activating mutations, and oncogenic fusions. Thus, the development of FGF/FGFR-targeting therapies is the focus of several basic, preclinical, and clinical studies.

Areas covered: This review will recapitulate the status of current FGF/FGFR-targeted drugs.

Expert commentary: Non-selective FGF/FGFR inhibitors have been approved for cancer treatment but evidence highlights various complications affecting their use in the clinical practice. It appears mandatory to identify FGF/FGFR alterations and appropriate biomarkers that may predict and monitor response to treatment, to establish the contribution of the FGF/FGFR system to the onset of mechanisms of drug resistance, and to develop effective combinations of FGF/FGFR inhibitors with other targeted therapies.     

A real-world study of the efficacy and safety of anti-programmed cell death-1 therapy combined with chemotherapy or targeted therapy in patients with advanced biliary tract cancer

BackgroundImmune checkpoint inhibitors (ICIs) represent a breakthrough in cancer treatment. However, they have rarely been used to treat biliary tract cancer (BTC). In the current study, we aimed to evaluate and compare the efficacy and safety of anti-programmed cell death-1 (PD-1) therapy used alone or in combination with chemotherapy or targeted therapy in the treatment of advanced BTC.MethodsPatients with advanced BTC who were treated either with anti-PD-1 therapy alone or anti-PD-1 therapy plus chemotherapy or targeted therapy between December, 2015 and October, 2017 were retrospectively screened for eligibility. Patients who had previously received treatment with any agent targeting T-cell co-stimulation or immune checkpoints were excluded. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and safety were evaluated.ResultsA total of 37 patients were included in this study (15 cases in the monotherapy group and 22 cases in the combination group). Patients in the combination group had significantly longer OS [median, 8.2 vs. 3.6 months, HR 0.47 (0.20–1.10), P=0.011] and PFS (median, 3.9 vs. 2.0 months, HR 0.58 (0.28–1.19), P=0.034) than patients in the monotherapy group. The ORR was 18.2% (4/22) and 0% in the combination group and monotherapy group, respectively, and the difference was not significant (P=0.131). Furthermore, no significant difference was found between the two groups with respect to the incidence of grade 3–4 treatment-related adverse events (P=0.388).ConclusionsAnti-PD-1 therapy plus chemotherapy or targeted therapy is an effective and tolerable treatment for patients with advanced BTC and is promising as a first-line treatment or beyond.     

Interference with EGFR signaling: paradigm for improving radiation response in cancer treatment

The introduction of biologically active agents that interfere with the epidermal growth factor receptor (EGFR) provides a promising opportunity to improve cancer treatment outcomes. Several EGFR-selective agents, such as humanized monoclonal antibodies and small molecule, orally available tyrosine kinase inhibitors have shown antitumor activity in early clinical trials in advanced cancer patients. Preclinical studies have demonstrated enhanced radiation- and chemotherapy-induced tumor cytotoxicity when EGFR antagonists are implemented. More broadly, recent clinical trials have confirmed improved survival with combinations of HER-2 (a member of the ErbB family of receptors) targeted antibodies and chemotherapy in patients with advanced breast cancer. A landmark trial combining C225 antiEGFR antibody with radiation therapy for patients with locally advanced head and neck cancer has just completed accrual. Thus, emerging rapidly are cancer treatment strategies based on an improved understanding of the specific cellular and molecular abnormalities of individual tumors.     

Epidermal growth factor receptor and K-Ras mutations and resistance of lung cancer to insulin-like growth factor 1 receptor tyrosine kinase inhibitors

BACKGROUND:

Most patients with nonsmall cell lung cancer (NSCLC) have responded poorly to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). The authors investigated the involvement of insulinlike growth factor 1 receptor (IGF‐1R) signaling in primary resistance to EGFR TKIs and the molecular determinants of resistance to IGF‐1R TKIs.

METHODS:

Phosphorylated IGF‐1R/insulin receptor (pIGF‐1R/IR) was immunohistochemically evaluated in an NSCLC tissue microarray. The authors analyzed the antitumor effects of an IGF‐1R TKI (PQIP or OSI‐906), either alone or in combination with a small‐molecular inhibitor (PD98059 or U0126) or with siRNA targeting K‐Ras or mitogen‐activated protein kinase/extracellular signal‐regulated kinase kinase (MEK), in vitro and in vivo in NSCLC cells with variable histologic features and EGFR or K‐Ras mutations.

RESULTS:

pIGF‐1R/IR expression in NSCLC specimens was associated with a history of tobacco smoking, squamous cell carcinoma histology, mutant K‐Ras, and wild‐type (WT) EGFR, all of which have been strongly associated with poor response to EGFR TKIs. IGF‐1R TKIs exhibited significant antitumor activity in NSCLC cells with WT EGFR and WT K‐Ras but not in those with mutations in these genes. Introduction of mutant K‐Ras attenuated the effects of IGF‐1R TKIs on NSCLC cells expressing WT K‐Ras. Conversely, inactivation of MEK restored sensitivity to IGF‐TKIs in cells carrying mutant K‐Ras.

CONCLUSIONS:

The mutation status of both EGFR and K‐Ras could be a predictive marker of response to IGF‐1R TKIs. Also, MEK antagonism can abrogate primary resistance of NSCLC cells to IGF‐1R TKIs. Cancer 2012. © 2012 American Cancer Society.     

EGFR-TKIs 在晚期EGFR受体突变肺鳞癌患者中的临床应用

目的:探讨表皮生长因子受体酪氨酸激酶抑制剂（epidermal growth factor receptor tyrosine kinase inhibitors,EGFR-TKIs）对具有表皮生长因子受体（epidermal growth factor receptor ,EGFR）突变的晚期肺鳞癌患者临床疗效。方法:回顾性分析首都医科大学附属北京胸科医院2010年1 月至2016年7 月收治的2 317 肺鳞癌患者,筛选出有明确随访记录的7 例确诊具有EGFR 突变的肺鳞癌患者,使用EGFR-TKI 如吉非替尼、厄洛替尼治疗,直至疾病进展（progressive disease ,PD）。 结果:使用EGFR-TKI 治疗后,患者客观缓解率（objectire response rate ,ORR ）42.9% ,疾病控制率（disease control rate ,DCR ）100%（7/ 7）,中位无进展生存期6.1 个月。结论:EGFR-TKI 对EGFR 突变的肺鳞癌患者具有一定临床疗效。但本研究病例数少仅有7 例,亟需更多的病例来进行补充研究及验证上述结论。      

Recent advances for the treatment of pancreatic and biliary tract cancer after first-line treatment failure

Here, we evaluate clinical trials on chemotherapy for patients with pancreatic or biliary tract cancer after first-line treatment failure. Clinical trials on conventional and innovative medical treatments for progressive pancreatic and biliary cancer were analyzed. Metronomic chemotherapy, which consists of the administration of continuative low-dose of anticancer drugs, was also considered. A significant extension of overall survival was achieved with second-line, regimens in patients with gemcitabine-refractory pancreatic cancer. Moreover, many Phase II studies, including chemotherapy and target molecules and immunotherapy, have reported promising results, in both pancreatic and biliary cancer. However, data in these patients’ setting are very heterogeneous, and only few randomized studies are available.     

The small GTPase ADP-Ribosylation Factor 1 mediates the sensitivity of triple negative breast cancer cells to EGFR tyrosine kinase inhibitors

The clinical use of EGFR-targeted therapy, in triple negative breast cancer patients, has been limited by the development of resistance to these drugs. Although activated signaling molecules contribute to this process, the molecular mechanisms remain relatively unknown. We have previously reported that the small GTPase ADP-Ribosylation Factor 1 (ARF1) is highly expressed in invasive breast cancer cells and acts as a molecular switch to activate EGF-mediated responses. In this study, we aimed at defining whether the high expression of ARF1 limits sensitivity of these tumor cells to EGFR inhibitors, such as gefitinib. Here, we show that the knock down of ARF1 expression or activity decreased the dose and latency time required by tyrosine kinase inhibitors to induce cell death. This may be explained by the observation that the depletion of ARF1 suppressed gefitinib-mediated activation of key mediators of survival such as ERK1/2, AKT and Src, while enhancing cascades leading to apoptosis such as the p38MAPK and JNK pathways, modifying the Bax/Bcl2 ratio and cytochrome c release. In addition, inhibiting ARF1 expression and activation also results in an increase in gefitinib-mediated EGFR internalization and degradation further limiting the ability of this receptor to promote its effects. Interestingly, we observed that gefitinib treatment resulted in the enhanced activation of ARF1 by promoting its recruitment to the receptor AXL, an important mediator of EGFR inhibition suggesting that ARF1 may promote its pro-survival effects by coupling to alternative mitogenic receptors in conditions where the EGFR is inhibited. Together our results uncover a new role for ARF1 in mediating the sensitivity to EGFR inhibition and thus suggest that limiting the activation of this GTPase could improve the therapeutic efficacy of EGFR inhibitors.     

一线用药的EGFR－TKIs与化疗治疗基因突变型NSCLC疗效比较的Meta分析

目的：系统评价表皮生长因子受体酪氨酸激酶抑制剂（epidermal growth factor receptor tyrosine kinase inhibitors,EGFR－TKIs）与化疗一线治疗基因突变型非小细胞肺癌（non－small cell lung cancer,NSCLC）患者的疗效比较。方法：自PubMed、Cochrane Library、Embase中检索相关的主题词及自由词,收集EGFR－TKIs与化疗相比一线治疗基因突变型NSCLC疗效的随机对照研究（randomized controlled trials,RCT）。按纳入标准及排除标准筛选文献,采用Cochrane偏倚风险评估表对纳入文献进行质量评价,自纳入文献中提取有效数据,应用RevMan 5．3．5和STATA 12．0分析基因突变型晚期NSCLC患者在EGFR－TKIs治疗中的疗效。敏感性分析和发表偏倚分析以评价结果的稳定性和可靠性。结果：共纳入5篇RCT,共1091例患者,对于EG-FR基因变异型晚期NSCLC患者：EGFR－TKIs一线治疗与化疗相比,有较好的无进展生存期（PFS）、客观反应率（ORR）,但总体生存期（OS）两者无明显差异。结论：EGFR基因突变的晚期NSCLC患者接受一线EGFR－TKIs治疗相比化疗获益更多。     

Sequential therapy of portal vein embolization and systemic chemotherapy for locally advanced perihilar biliary tract cancer

BackgroundCurative resection is the only potential treatment for cure in patients with perihilar biliary tract cancer (PBTC). However, post hepatectomy liver failure (PHLF) due to insufficient future liver remnant volume (FRLV) remains a lingering risk even after portal vein embolization (PVE). This study aimed to investigate the feasibility and efficacy of a sequential treatment strategy consisting of PVE followed by preoperative chemotherapy before surgery.MethodsBetween April 2019 and December 2021, 15 patients with locally advanced PBTC (LA-PBTC) underwent sequential treatment consisting of PVE followed by preoperative chemotherapy. The feasibility and efficacy, including resection rate, changes of FRLV, and chemotherapeutic effect, were investigated retrospectively.ResultsThirteen of 15 patients (86.6%) underwent curative resection. The median duration time between PVE and surgery was 144 days. FRLV/TLV ratio was 31.3% at prePVE, 38.4%, at two weeks after PVE, and 45.7% before surgery, respectively. There was significant increase in FRLV/TLV ratio two weeks after PVE. Additional increase in FRLV/TLV ratio was significantly achieved before surgery. PHLF occurred in 5 patients (38.4%). Pathological complete response was found in 2 of 13 patients (15.3%).ConclusionsSequential PVE and systemic chemotherapy contribute to the sufficient hypertrophy of FRLV without compromising resectability in patients with LA-PBTC.     

Icotinib might be effective for the treatment of leptomeningeal carcinomatosis in non-small cell lung cancer with sensitive EGFR mutations

BackgroundThe incidence of leptomeningeal carcinomatosis (LMC) has increased in patients with metastatic non-small cell lung cancer (NSCLC). This study aimed to evaluate the effect of icotinib in the treatment of LMC.MethodsTwenty-one NSCLC patients diagnosed with LMC and treated with icotinib were retrospectively reviewed.ResultsAn exon 21 point mutation and an exon 19 deletion of EGFR were found in 10 and 11 patients, respectively. A standard dose of icotinib (125 mg/day, three times a day) was prescribed to 16 patients without previous icotinib therapy. A double dose of icotinib was prescribed to five patients who developed LMC during icotinib therapy with a standard dose. Eighteen of 20 patients showed improvement of dizziness and headache. Seventeen of 21 patients had an improved Eastern Cooperative Oncology Group performance status (ECOG PS) score after icotinib treatment. The median overall survival of the patients after the diagnosis of LMC was 10.1 months (95% confidence interval (CI): 8.4–12.0 months). Univariate analysis showed that the ECOG PS score, parenchymal brain metastasis, and previous icotinib administration were significantly associated with patient survival. Multivariate analysis also demonstrated that the ECOG PS score was an independent predictor for survival.ConclusionOur results suggest that icotinib is effective for the treatment of LMC from NSCLC with an EGFR mutation, especially for patients with a good ECOG PS score.     

Different interventional time of hepatic arterial infusion with PD-1 inhibitor for advanced biliary tract cancer: a multicenter retrospective study

This study investigated the efficacy and safety of hepatic artery infusion chemotherapy (HAIC) combined with PD-1 immunotherapy for advanced biliary tract cancer (BTC) and evaluated the optimal timing of HAIC. A total of 36 unresectable BTC patients treated with HAIC and PD-1 inhibitors between September 2019 and July 2021 were included in this study. Overall survival (OS), progression-free survival (PFS), tumor response, and adverse events (AEs) were investigated. Overall, 52.8% patients with advanced BTC were in stage IV, 23 patients who progressed after receiving PD-1 inhibitor had undergone HAIC, and 23 patients have received 2 or more lines of therapy. The median OS was 8.8 months (range: 4.0-24.0 months), and the median PFS was 3.7 months. The objective response rate and disease control rate were 11.5% and 76.9%, respectively. In the subgroup analysis, patients who treated with HAIC early without progression after immunotherapy were associated with a trend toward better OS (median 13.0 vs. 7.6 months; P = 0.004) and PFS (median 7.9 vs. 3.6 months; P = 0.09) compared to with HAIC with progression after PD-1 treatment. No treatment-related deaths occurred. A total of 44.4% of the patients experienced grade 3 or 4 AEs. We conclude that the combination of HAIC and PD-1 inhibitors is safe and effective. Early HAIC combined with immunotherapy can effectively prolong the overall survival of patients with advanced BTC.     

非小细胞肺癌EGFR-TKIs耐药——小细胞肺癌转化的机制和治疗

肺癌是当前死亡率最高的恶性肿瘤之一。表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKIs）明显提高了晚期非小细胞肺癌（NSCLC）患者的生活质量,延长了生存期。EGFR基因优势突变的NSCLC患者临床获益明显,然而由于耐药产生,患者的中位无进展生存期（PFS）仅1年左右。最近,有文献报道EGFR TKIs耐药的机制之一是NSCLC转化为小细胞肺癌（SCLC）。本文对这种现象进行了分析总结,探讨了其转化的可能机制。根据EGFR-TKIs耐药后的处理方法和病理表型转化患者的治疗报道,探讨NSCLC EGFR-TKIs耐药后转化为SCLC患者的治疗策略。     

非小细胞肺癌EGFR不同突变状态的脑转移发生特点及治疗

目的 有研究显示,表皮生长因子受体(epidermal growth factor receptor,EGFR)的突变状态,与非小细胞肺癌(non-small cell lung cancer,NSCLC)脑转移存在相关性.本研究进一步探讨EGFR不同突变状态的NSCLC患者,脑转移发生的特点以及相应的治疗.方法 选取2009-04-01-2014-12-01中国人民解放军火箭军总医院肿瘤科病理确诊断的231例NSCLC患者的临床资料,进行回顾性研究.并应用实时定量PCR方法,检测上述患者的EGFR突变状态.利用x2检验比较EGFR不同突变状态的患者,脑转移特点的差异.Kaplan-Meier法进行生存分析.结果 EGFR检测结果示野生型119例,18、19、20、21号外显子及19/21双突变的分别有3例、58例、5例、42例和4例.19号外显子突变患者的脑转移发生率(55.2％)显著高于野生型患者(41.2％),P=0.04.伴21号外显子突变＞3个脑转移病灶患者(47.6％)的比例显著高于野生型患者(28.6％),P＜0.01.此外,伴21号外显子突变患者的中位脑转移年龄(63岁)也显著高于野生型患者(52岁),P=0.02.对于伴有EGFR突变的脑转移患者,脑转移后接受过酪氨酸激酶抑制剂(tyro-sine kinase inhibitors,TKIs)的患者,其中位脑转移后生存期显著长于接受常规化疗的患者(未达到vs 9个月),P=0.01.结论 伴EGFR特定位点突变的患者有更高的脑转移发生率、脑转移数目及脑转移时年龄.TKIs可改善伴EG-FR突变脑转移患者的预后.     

RAC1 inhibition as a therapeutic target for gefitinib‐resistant non‐small‐cell lung cancer

Although epidermal growth factor receptor (EGFR)‐tyrosine kinase inhibitors (EGFR‐TKI), including gefitinib, provide a significant clinical benefit in non‐small‐cell lung cancer (NSCLC) patients, the acquisition of drug resistance has been known to limit the efficacy of EGFR‐TKI therapy. In this study, we demonstrated the involvement of EGF‐EGFR signaling in NSCLC cell migration and the requirement of RAC1 in EGFR‐mediated progression of NSCLC. We showed the significant role of RAC1 pathway in the cell migration or lamellipodia formation by using gene silencing of RAC1 or induction of constitutive active RAC1 in EGFR‐mutant NSCLC cells. Importantly, the RAC1 inhibition suppressed EGFR‐mutant NSCLC cell migration and growth in vitro, and growth in vivo even in the gefitinib‐resistant cells. In addition, these suppressions by RAC1 inhibition were mediated through MEK or PI3K independent mechanisms. Collectively, these results open up a new opportunity to control the cancer progression by targeting the RAC1 pathway to overcome the resistance to EGFR‐TKI in NSCLC patients.     

Efficacy and mechanism of action of the tyrosine kinase inhibitors gefitinib,lapatinib and neratinib in the treatment of HER2-positive breast cancer: preclinical and clinical evidence

An increasing number of tumors, including breast cancer, overexpress proteins of the epidermal growth factor receptor (EGFR) family. The interaction between family members activates signaling pathways that promote tumor progression and resistance to treatment. Human epidermal growth factor receptor type II (HER2) positive breast cancer represents a clinical challenge for current therapy. It has motivated the development of novel and more effective therapeutic EGFR family target drugs, such as tyrosine kinase inhibitors (TKIs). This review focuses on the effects of three TKIs mostly studied in HER2- positive breast cancer, lapatinib, gefitinib and neratinib. Herein, we discuss the mechanism of action, therapeutic advantages and clinical applications of these TKIs. To date, TKIs seem to be promising therapeutic agents for the treatment of HER2-overexpressing breast tumors, either as monotherapy or combined with other pharmacological agents.     

Phase II study of gemcitabine,oxaliplatin in combination with panitumumab in KRAS wild-type unresectable or metastatic biliary tract and gallbladder cancer

Background:

Current data suggest that platinum-based combination therapy is the standard first-line treatment for biliary tract cancer. EGFR inhibition has proven beneficial across a number of gastrointestinal malignancies; and has shown specific advantages among KRAS wild-type genetic subtypes of colon cancer. We report the combination of panitumumab with gemcitabine (GEM) and oxaliplatin (OX) as first-line therapy for KRAS wild-type biliary tract cancer.

Methods:

Patients with histologically confirmed, previously untreated, unresectable or metastatic KRAS wild-type biliary tract or gallbladder adenocarcinoma with ECOG performance status 0–2 were treated with panitumumab 6 mg kg⁻¹, GEM 1000 mg m⁻² (10 mg m⁻² min⁻¹) and OX 85 mg m⁻² on days 1 and 15 of each 28-day cycle. The primary objective was to determine the objective response rate by RECIST criteria v.1.1. Secondary objectives were to evaluate toxicity, progression-free survival (PFS), and overall survival.

Results:

Thirty-one patients received at least one cycle of treatment across three institutions, 28 had measurable disease. Response rate was 45% and disease control rate was 90%. Median PFS was 10.6 months (95% CI 5–24 months) and median overall survival 20.3 months (95% CI 9–25 months). The most common grade 3/4 adverse events were anaemia 26%, leukopenia 23%, fatigue 23%, neuropathy 16% and rash 10%.

Conclusions:

The combination of gemcitabine, oxaliplatin and panitumumab in KRAS wild type metastatic biliary tract cancer showed encouraging efficacy, additional efforts of genetic stratification and targeted therapy is warranted in biliary tract cancer.