Acquired MET D1228N Mutations Mediate Crizotinib Resistance in Lung Adenocarcinoma with ROS1 Fusion: A Case Report

Patients with non‐small cell lung cancer (NSCLC) containing ROS1 fusions can have a marked response to the ROS1‐targeted tyrosine kinase inhibitors (TKIs), such as crizotinib. Common resistance mechanisms of ROS1‐fusion targeted therapy are acquired mutations in ROS1. Along with the use of next‐generation sequencing in the clinical management of patients with NSCLC during sequential targeted therapy, many mechanisms of acquired resistance have been discovered in patients with activated tyrosine kinase receptors. Besides acquired resistance mutations, bypass mechanisms of resistance to epidermal growth factor receptor (EGFR)‐TKI treatment are common in patients with EGFR mutations. Here we describe a patient with metastatic lung adenocarcinoma with CD74‐ROS1 fusion who initially responded to crizotinib and then developed resistance by the acquired mutation of D1228N in the MET kinase domain, which showed short‐term disease control for cabozantinib.Key Points

• The D1228N point mutation of MET is an acquired mutation for crizotinib resistance.
• The patient obtained short‐term clinical benefit from cabozantinib therapy after resistance to crizotinib.
• The clinical use of next‐generation sequencing could maximize the benefits of precision medicine in patients with cancer.

     

Renal Effects of Crizotinib in Patients With ALK-Positive Advanced NSCLC

IntroductionWe retrospectively analyzed the effects of crizotinib on serum creatinine and creatinine-based estimated glomerular filtration rate (eGFR) in patients with anaplastic lymphoma kinase–positive advanced NSCLC across four trials (NCT00585195, NCT00932451, NCT00932893, and NCT01154140).MethodsChanges from baseline data in serum creatinine and eGFR, calculated using the Chronic Kidney Disease Epidemiology Collaboration creatinine-based equation, were assessed over time. eGFR was graded using standard chronic kidney disease criteria.ResultsMedian serum creatinine increased from 0.79 mg/dL at baseline to 0.93 mg/dL after 2 weeks of treatment (median percentage increase from baseline, 21.2%), was stable from week 12 (0.96 mg/dL) to week 104 (1.00 mg/dL), and decreased to 0.90 mg/dL at 28 days after last dose (median percentage increase from baseline, 13.1%). Median eGFR decreased over time (96.42, 80.23, 78.06 and 75.45 mL/min/1.73 m² at baseline, week 2, week 12, and week 104, respectively) and increased to 83.02 mL/min/1.73 m² at 28 days after the last dose. Median percentage decrease from baseline was 14.9%, 17.0%, and 10.4% at week 2, week 12, and 28 days after last dose of crizotinib, respectively. Overall, 12.6% of patients had a shift from eGFR grade less than or equal to 3a (≥45 mL/min/1.73 m²) at baseline to greater than or equal to 3b (<45 mL/min/1.73 m²) post-baseline.ConclusionsCrizotinib resulted in a decline in creatinine-based estimates of renal function mostly over the first 2 weeks of treatment. However, there was minimal evidence of cumulative effects with prolonged treatment and these changes were largely reversible following treatment discontinuation, consistent with previous reports suggesting this may be predominantly an effect on creatinine secretion as opposed to true nephrotoxicity.     

Comparative efficacy of first-line ceritinib and crizotinib in advanced or metastatic anaplastic lymphoma kinase-positive non-small cell lung cancer: an adjusted indirect comparison with external controls

Objective: In the absence of head-to-head trials, this study indirectly compared progression free survival (PFS) and overall survival (OS) between ceritinib and crizotinib among patients with previously untreated advanced anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC).

Methods: A matching-adjusted indirect comparison method was implemented to adjust for cross-trial differences in patient characteristics between ASCEND-4 and PROFILE 1014 trials. Patient-level data from ASCEND-4 and published summary data from PROFILE 1014 were used. Patients in ASCEND-4 were reweighted to match average baseline characteristics (i.e. age, sex, race, tumor histology, ECOG score, smoking status, extent of disease, and presence of brain metastases) reported for PROFILE 1014 patients using propensity score weighting. PFS and OS were then compared between balanced populations.

Results: ASCEND-4 included more current smokers (8.0% vs 4.4%) and fewer patients under the age of 65 years (78.5% vs 84.0%) compared to PROFILE 1014. After matching, these and all other patient characteristics were balanced between the two trial populations. Compared to crizotinib, ceritinib was associated with a significantly longer PFS (hazard ratio [95% confidence interval] (HR [CI])?=?0.64 [0.47–0.87]; median PFS: 25.2 vs 10.8 months, log-rank p-value?=?0.003). OS did not differ significantly, with a HR of 0.82 [0.54–1.27] for ceritinib compared to crizotinib.

Conclusions: In the adjusted indirect comparison with external controls, the second generation ALK inhibitor, ceritinib, was associated with a significantly prolonged PFS compared to crizotinib as first-line treatment for ALK-positive NSCLC.     

表皮生长因子受体酪氨酸激酶抑制剂治疗晚期非小细胞肺癌的效果及对免疫功能的调节作用

目的探讨表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)治疗晚期非小细胞肺癌(NSCLC)患者的效果及对免疫功能的调节作用。方法选取2017年1月至2019年12月山西省肿瘤医院呼吸二科收治的100例经病理诊断为晚期(ⅢA~Ⅳ期)NSCLC的患者,男60例,女40例,年龄(58.94±12.33)岁,年龄范围为35~72岁。根据基因检测结果,依据患者基因突变情况分为EGFR-TKI组(n=48)、克唑替尼组(n=7)与联合治疗组(n=45),EGFR-TKI组采用EGFR-TKI治疗,克唑替尼组采用克唑替尼治疗,联合治疗组采用多西他赛联合顺铂治疗。比较三组患者的治疗效果、不良反应发生情况、淋巴细胞亚群[表面抗原分化簇3(CD3⁺)、表面抗原分化簇4(CD4⁺)、表面抗原分化簇8(CD8⁺)、CD4⁺/CD8⁺]和生活质量[健康调查简表(SF-36)评分、卡氏行为能力状况量表(KPS)评分]。结果 EGFR-TKI组的有效率(68.8%)、疾病控制率(87.5%)和克唑替尼组的有效率(71.4%)、疾病控制率(85.7%)高于联合治疗组[(31.1%)、(44.4%)],差异有统计学意义(P<0.05)。三组患者不良反应发生率比较,差异无统计学意义(P>0.05)。治疗后,EGFR-TKI组CD3⁺[(49.67±7.35)%]、CD4⁺[(42.00±5.17)%]、CD4⁺/CD8⁺(1.97±0.51)高于治疗前[(28.73±4.92)%]、[(24.16±3.90)%、(1.30±0.49)],克唑替尼组CD3⁺[(51.21±7.72)%]、CD4⁺[(40.79±4.37)%]、CD4⁺/CD8⁺(2.01±0.48)高于治疗前[(28.42±4.52)%]、[(23.85±3.73)%、(1.30±0.52)],联合治疗组CD3⁺[(41.05±6.37)%]、CD4⁺[(34.52±4.41)%]、CD4⁺/CD8⁺(1.67±0.45)高于治疗前[(28.62±5.36)%]、[(23.65±3.66)%、(1.28±0.53)],三组患者的CD8⁺[(16.71±1.79)%、(15.90±1.93)%、(21.28±2.40)%]均低于治疗前[(26.44±3.20)%、(26.42±3.11)%、(26.32±3.05)%];治疗后,EGFR-TKI组的SF-36评分[(84.26±6.70)分]、卡氏评分[(86.29±7.92)分]和克唑替尼组的SF-36评分[(82.85±5.72)分]、卡氏评分[(87.84±7.28)分]均高于联合治疗组[(67.19±6.33)分、(73.56±8.16)分],差异均有统计学意义(P<0.05)。结论靶向药物在晚期非小细胞肺癌患者治疗中具有较为显著的效果,不良反应发生率低,可改善患者免疫功能,值得临床推广。