Clinical characteristics and response to tyrosine kinase inhibitors of patients with non-small cell lung cancer harboring uncommon epidermal growth factor receptor mutations

Objective： To investigate the clinical features of patients with non-small cell lung cancer（NSCLC） harboring uncommon epidermal growth factor receptor（EGFR） mutations, and the treatment outcomes of EGFR tyrosine kinase inhibitors（TKIs） in these patients.Methods： We retrospectively analyzed the data of 128 NSCLC patients pathologically diagnosed with uncommon EGFR mutation in the Department of Pathology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences ＆ Peking Union Medical College and Beijing Hospital from January 2010 to December 2015, including 40 advanced patients who received EGFR-TKI.Results： Among the total 128 patients, 11 patients were non-adenocarcinoma, including squamous carcinoma（3.9%）, adenosquamous carcinoma（2.3%）, large cell carcinoma（0.8%）, and composite neuroendocrine carcinoma（1.6%）. Single mutations accounted for 75.0%（96/128）, including G719X（29.7%）, S768I（18.0%）, 20 exon insertion（13.3%）, L861Q（12.5%）, De novo T790M（0.8%）, and T725（0.8%）. Thirty-two patients harbored complex mutations. Forty advanced patients received EGFR-TKI, the objective response rate（ORR） was 20.0%,the disease control rate（DCR） was 85.0%, and the progression-free survival（PFS） was 6.4 [95% confidence interval（95% CI）, 4.8–7.9] months. The exploratory analysis of tumor response and PFS in 33 patients with G719X/S768I/L861 Q subtypes showed that ORR was 21.2%（7/33）, the DCR was 93.9%（31/33）, and PFS was 7.6（95% CI, 5.8–9.4） months. Patients with exon 20 insertion mutation and De novo T790 M experienced rapid disease progression with PFS no more than 2.7 months.Conclusions： Uncommon EGFR-mutant NSCLCs are heterogeneous, EGFR-TKIs can have different efficacy in this specific subtype, and thus further individual assessment is required for each case.

500例肺癌患者首诊症状及其影响因素分析

背景与目的肺癌的发病率与死亡率不断升高,本研究探讨初诊肺癌患者临床特征,特别是首诊症状对诊断及后续治疗选择的影响。方法回顾性分析自2017年3月-2017年5月我院胸内科门诊就诊的500例肺癌患者,分析其临床特征包括首发症状、分期、生物标志物、病理等对后续治疗选择影响。结果女性(53.3%)、腺癌(74.4%)、吸烟者(58%)多见,大部分患者(98.2%)体力状态评分为0分-1分。生物标志物检测58.2%(n=291),其中表皮生长因子受体(epidermal growth factor receptor,EGFR)突变61.2%(178/291),间变性淋巴瘤激酶(anaplasticlymphoma kinase,ALK)融合基因阳性4.1%(12/291)。不同吸烟状况、是否有症状、病理分型、疾病分期和是否有突变是影响后续治疗的主要因素。结论就诊时有典型症状的患者确诊时间更短,吸烟状况、肺癌相关症状、病理、疾病分期及突变状况是影响后续治疗的主要因素。

Sequential therapy according to distinct disease progression patterns in advanced ALK-positive non-small-cell lung cancer after crizotinib treatment

Objective: Crizotinib is recommended as the first-line therapy for advanced anaplastic lymphoma kinase(ALK)-positive non-small-cell lung cancer(NSCLC). Despite its initial efficacy, patients ultimately acquire resistance to crizotinib within 1 year. In such patients, the optimal sequential therapy after crizotinib treatment remains unknown. This study explored which sequential therapy option confers the greatest benefit.Methods: A total of 138 patients with advanced ALK-positive NSCLC resistant to crizotinib were studied. Based on patterns of disease progression of metastases, patients were divided into 3 groups: brain progression, non-liver progression, and liver progression. Sequential therapies included crizotinib continuation plus local therapy, nextgeneration ALK inhibitors(ALKi's), and chemotherapy. The primary endpoint was overall survival(OS) from the time of crizotinib resistance to death or last follow-up.Results: The 138 patients included 64 cases with progression in brain, 57 cases in non-liver sites and 17 cases in liver. A significant difference in OS was observed among the distinct progression pattern(median OS, 25.4 months in brain, 15.8 months in non-liver, and 10.8 months in liver, respectively, P=0.020). The difference in OS among sequential therapies was statistically significant in the non-liver progression group(median OS, 27.6 months with next-generation ALKi's, 13.3 months with crizotinib continuation, and 10.8 months with chemotherapy,respectively, P=0.019). However, crizotinib continuation plus local therapy seems to provide non-inferior median OS compared with next-generation ALKi's for patients with brain progression(median OS, 28.9 months vs.32.8 months, P=0.204). And no significant differences in OS were found in patients with progression in liver(P=0.061).Conclusions: Crizotinib continuation together with local therapy might be a feasible strategy for patients with progression in brain beyond crizotinib resistance, as well as next-generation ALKi's. Next-generation ALKi's tended to provide a survival benefit in patients with non-liver progression.

Impact of crizotinib on long-term survival of ALK-positive advanced non-small-cell lung cancer: A Chinese multicenter cohort study

Objective: Crizotinib has demonstrated promising efficacy in patients with anaplastic lymphoma kinase(ALK)-positive non-small-cell lung cancer(NSCLC) in clinical trials. We conducted this retrospective multicenter study to assess the outcomes of crizotinib therapy in, to our knowledge, a large sample cohort of patients with ALKpositive advanced NSCLC.Methods: We reviewed the medical records of 484 unselected ALK-positive NSCLC patients treated with crizotinib at 5 cancer centers in China from January 2013 to November 2017. Clinical data were collected from the initiation of crizotinib therapy to Response Evaluation Criteria in Solid Tumors(RECIST)-defined progressive disease(PD).Results: A total of 428 eligible ALK-positive NSCLC patients were enrolled, 273(63.8%) of whom received crizotinib as first-line treatment. The median progression-free survival(PFS) and overall survival(OS) from the initiation of crizotinib treatment were 14.4 [95% confidence interval(95% CI), 12.4-16.4] months and 53.4(95%CI, 33.7-73.1) months, respectively. In subgroup analyses, patients who received crizotinib as first-line treatment showed a higher disease control rate(DCR) and a longer median OS compared with second-/later-line crizotinib treatment(94.8% and OS not reached vs. 89.0% and 40.5 months, respectively). For 261 patients with RECISTdefined PD, multivariate Cox analysis revealed that in patients who received first-line crizotinib therapy, continued crizotinib beyond progressive disease(CBPD) and next-generation ALK inhibitors after crizotinib failure were associated with improved survival.Conclusions: This study has demonstrated the clinically meaningful benefit of crizotinib treatment in a large cohort of Chinese ALK-positive NSCLC patients. CBPD and next-generation ALK inhibitor treatment may provide improved survival after RECIST-defined progression on crizotinib.

The commensal consortium of the gut microbiome is associated with favorable responses to anti-programmed death protein 1 (PD-1) therapy in thoracic neoplasms

Objective:Immune checkpoint inhibitors have revolutionized cancer therapy for multiple types of solid tumors,but as expected,a large percentage of patients do not show durable responses.Biomarkers that can predict clinical responses to immunotherapies at diagnosis are therefore urgently needed.Herein,we determined the associations between baseline gut commensal microbes and the clinical treatment efficiencies of patients with thoracic neoplasms during anti-programmed death protein 1(PD-1)therapy.Methods:Forty-two patients with advanced thoracic carcinoma who received anti-PD-1 treatment were enrolled in the study.Baseline and time-serial stool samples were analyzed using 16S ribosomal RNA gene sequencing.Tumor responses,patient progression-free survival,and overall survival were used to measure clinical outcomes.Results:The diversities of the baseline gut microbiota were similar between responders(n=23)and nonresponders(n=19).The relative abundances of the Akkermansiaceae,Enterococcaceae,Enterobacteriaceae,Carnobacteriaceae and Clostridiales Family XI bacterial families were significantly higher in the responder group.These 5 bacterial families acted as a commensal consortium and better stratified patients according to clinical responses(P=0.014).Patients with a higher abundance of commensal microbes had prolonged PFS(P=0.00016).Using multivariable analysis,the abundance of the commensal consortium was identified as an independent predictor of anti-PD-1 immunotherapy in thoracic neoplasms(hazard ratio:0.17;95%confidence interval:0.05–0.55;P=0.003).Conclusions:Baseline gut microbiota may have a critical impact on anti-PD-1 treatment in thoracic neoplasms.The abundance of gut commensal microbes at diagnosis might be useful for the early prediction of anti-PD-1 immunotherapy responses.

Adjuvant and neo‐adjuvant immunotherapy in resectable non‐small cell lung cancer (NSCLC): Current status and perspectives

Surgery followed by adjuvant chemotherapy is the standard of care for selectedpatients with early‐stage or locally advanced non‐small cell lung cancer(NSCLC). However, many of these patients still experience postoperativerecurrence at 5 years. At present, peri‐operative treatment methods areemerging to prevent early relapse, such as targeted therapy and immunotherapy.Investigation on predictive biomarkers of responses to adjuvant andneoadjuvant therapies is also continuously ongoing. Immunotherapy representedby immune checkpoint inhibitors (ICIs), either by monotherapy or incombination with chemotherapy, has shown benefit in promoting pathologicalresponses and prolonging survival for patients with NSCLC without oncogenicmutations. Exploratory studies have also provided evidence regarding theselection of patients who benefit from ICI‐based perioperative treatment. Thisreview focuses on the existing data of current clinical trials of adjuvant andneoadjuvant strategies with ICIs in resectable NSCLC, the exploration ofpredictive biomarkers, and the perspectives and urgent challenges in thefuture.

Safety and activity of WX-0593(Iruplinalkib)in patients with ALK-or ROS1-rearranged advanced non-small cell lung cancer:a phase 1 dose-escalation and dose-expansion trial

WX-0593(Iruplinalkib)is a novel,highly selective oral ALK and ROS1 tyrosine kinase inhibitor(TKI).In this study,the safety,antitumor activity,and pharmacokinetics of WX-0593 were evaluated in advanced non-small cell lung cancer(NSCLC)patients with ALK or ROS1 rearrangement.In the dose-escalation phase and dose-expansion phase,patients were treated with WX-0593 until disease progression,unacceptable toxicity,or subject withdrawal.In the dose-escalation phase,the primary endpoints were maximum tolerated dose(MTD),dose-limiting toxicity(DLT),and safety assessed by investigators.In the dose-expansion phase,the primary endpoint was objective response rate(ORR)assessed by investigators.Between September 25,2017 and October 15,2018,a total of 153 patients received WX-0593 treatment.Two dose-limiting toxicities(DLTs)including one grade 3 QT interval prolonged and one grade 2 chronic heart failure were reported at the dose of 300 mg in one patient.MTD was not reached.Overall,140 of the 152(92%)patients experienced treatment-related adverse events(TRAEs)and 35 of the 152(23%)patients had TRAEs≥grade 3.The overall ORR was 59.3%(32 of 54)for the dose-escalation phase and 56.6%(56 of 99)for the dose-expansion phase.For patients who were ALK-rearranged and ALK TKI naive,the ORR were 81.0%(17 of 21)in the dose-escalation phase and 76.3%(29 of 38)in the dose-expansion phase,and for patients who previously received crizotinib as the only ALK TKI,the ORR were 38.1%(8 of 21)and 45.7%(21 of 46)for the two phases,respectively.For patients who were ROS1-rearranged,the ORR were 30.0%(3 of 10)in the dose-escalation phase and 44.4%(4 of 9)in the dose-expansion phase.WX-0593 showed favorable safety and promising antitumor activity in advanced NSCLC patients with ALK or ROS1 rearrangement.