驱动基因突变非小细胞肺癌免疫治疗的研究进展

随着肺癌靶点的发现和药物研发,靶向治疗改善了驱动基因突变非小细胞肺癌(NSCLC)的临床预后。同时,免疫检查点抑制剂在驱动基因阴性NSCLC中也取得了良好的疗效。虽然部分驱动基因突变患者从对应靶向治疗中明显获益,但对免疫治疗反应欠佳。在大部分免疫治疗临床研究和日常实践中,EGFR/ALK等驱动基因突变阳性的NSCLC患者也被排除在外,或者仅占少数。免疫治疗如何应用于驱动基因突变患者,以及如何在靶向治疗、化疗及免疫治疗中选择最佳治疗方案,制定最优治疗策略,对改善晚期驱动基因突变NSCLC患者预后至关重要。本文对不同基因突变肿瘤免疫微环境的特点及免疫治疗在不同基因突变的NSCLC患者中的应用进行简要综述。     

Targeting MET in Lung Cancer: Will Expectations Finally Be MET?

The hepatocyte growth factor receptor (MET) is a potential therapeutic target in a number of cancers, including NSCLC. In NSCLC, MET pathway activation is thought to occur through a diverse set of mechanisms that influence properties affecting cancer cell survival, growth, and invasiveness. Preclinical and clinical evidence suggests a role for MET activation as both a primary oncogenic driver in subsets of lung cancer and as a secondary driver of acquired resistance to targeted therapy in other genomic subsets. In this review, we explore the biology and clinical significance behind MET proto-oncogene receptor tyrosine kinase (MET) exon 14 alterations and MET amplification in NSCLC, the role of MET amplification in the setting of acquired resistance to EGFR tyrosine kinase inhibitor therapy in EGFR-mutant NSCLC, and the history of MET pathway inhibitor drug development in NSCLC, highlighting current strategies that enrich for biomarkers likely to be predictive of response. Whereas previous trials that focused on MET pathway–directed targeted therapy in unselected or MET-overexpressing NSCLC yielded largely negative results, more recent investigations focusing on MET exon 14 alterations and MET amplification have been notable for meaningful clinical responses to MET inhibitor therapy in a substantial proportion of patients.     

Therapeutic strategies for afatinib‐resistant lung cancer harboring HER2 alterations

Human epidermal growth factor receptor 2 (HER2) plays an important role in the pathogenesis of various cancers. HER2 alterations have been suggested to be a therapeutic target in non‐small‐cell lung cancer (NSCLC), just as in breast and gastric cancers. We previously reported that the pan‐HER inhibitor afatinib could be a useful therapeutic agent as HER2‐targeted therapy for patients with NSCLC harboring HER2 alterations. However, acquired resistance to afatinib was observed in the clinical setting, similar to the case for other HER inhibitors. Thus, elucidation of the mechanisms underlying the development of acquired drug resistance and exploring means to overcome acquired drug resistance are important issues in the treatment of NSCLC. In this study, we experimentally established afatinib‐resistant cell lines from NSCLC cell lines harboring HER2 alterations, and investigated the mechanisms underlying the acquisition of drug resistance. The established cell lines showed several unique afatinib‐resistance mechanisms, including MET amplification, loss of HER2 amplification and gene expression, epithelial‐to‐mesenchymal transition (EMT) and acquisition of cancer stem cell (CSC)‐like features. The afatinib‐resistant cell lines showing MET amplification were sensitive to the combination of afatinib plus crizotinib (a MET inhibitor), both in vitro and in vivo. The resistant cell lines which showed EMT or had acquired CSC‐like features remained sensitive to docetaxel, like the parental cells. These findings may provide clues to countering the resistance to afatinib in NSCLC patients with HER2 alterations.     

Targeting NTRK fusion in non-small cell lung cancer: rationale and clinical evidence

In the era of personalized medicine, the identification of targetable genetic alterations represented a major step forward in anticancer therapy. NTRK rearrangements represent the molecular driver of a subset of solid tumors, including 3% of non-small-cell lung cancers (NSCLCs). Preliminary data indicate that molecularly selected NSCLC patients harboring NTRK fusions derive an unprecedented clinical benefit from Trk-directed targeted therapies. The aim of this review is to describe the molecular biology of NTRK signaling pathway and to summarize the preclinical data on novel Trk inhibitors, touching upon the clinical development of these inhibitors for the treatment of advanced NSCLC, which have already shown encouraging anticancer activity and acceptable safety profile in early phase I clinical trials.     

非小细胞肺癌分子靶向治疗及其耐药

以吉非替尼和厄洛替尼为代表的表皮生长因子受体酪氨酸激酶抑制剂在非小细胞肺癌治疗中发挥重要作用,然而在临床前和临床研究中发现,许多患者对此类药物存在原发性耐药或获得性耐药,使其临床应用受到一定限制.目前许多研究致力于延缓、逆转耐药以及开发新的靶点,为非小细胞肺癌的靶向治疗提供了更多的可能.     

Asian Thoracic Oncology Research Group (ATORG) Expert Consensus Statement on MET Alterations in NSCLC: Diagnostic and Therapeutic Considerations

Non-small cell lung cancer (NSCLC) is a heterogeneous disease, with many oncogenic driver mutations, including de novo mutations in the Mesenchymal Epithelial Transition (MET) gene (specifically in Exon 14 [ex14]), that lead to tumourigenesis. Acquired alterations in the MET gene, specifically MET amplification is also associated with the development of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) resistance in patients with EGFR-mutant NSCLC. Although MET has become an actionable biomarker with the availability of MET-specific inhibitors in selected countries, there is differential accessibility to diagnostic platforms and targeted therapies across countries in Asia-Pacific (APAC).The Asian Thoracic Oncology Research Group (ATORG), an interdisciplinary group of experts from Australia, Hong Kong, Japan, Korea, Mainland China, Malaysia, the Philippines, Singapore, Taiwan, Thailand and Vietnam, discussed testing for MET alterations and considerations for using MET-specific inhibitors at a consensus meeting in January 2022, and in subsequent offline consultation.Consensus recommendations are provided by the ATORG group to address the unmet need for standardised approaches to diagnosing MET alterations in NSCLC and for using these therapies. MET inhibitors may be considered for first-line or second or subsequent lines of treatment for patients with advanced and metastatic NSCLC harbouring MET ex14 skipping mutations; MET ex14 testing is preferred within multi-gene panels for detecting targetable driver mutations in NSCLC. For patients with EGFR-mutant NSCLC and MET amplification leading to EGFR TKI resistance, enrolment in combination trials of EGFR TKIs and MET inhibitors is encouraged.     

Other signalization targets

Treatment decisions for patients with lung cancer have historically been based upon tumor morphological analysis. Over the past decade, some molecular alterations have been identified as being necessary and sufficient to drive tumor carcinogenesis. These “driver” mutations occur in genes that encode signaling proteins critical for cellular proliferation and survival. Epidermal growth factor (EGF) receptor (EGFR) mutations are the best illustration of the therapeutic relevance of identifying such molecular clusters of lung cancer based on driver genetic alterations that predict the efficacy of specific tyrosine kinase inhibitors, a strategy referred to as “personalized medicine.” Besides EGFR and ALK, other genes harboring driver molecular alterations have been identified as part of integrated genomic studies of lung cancers. The objectives of this review are (1) to provide the reader with preclinical and clinical data on these new oncogenic mutations, focusing on druggable ones; (2) to discuss the dynamic nature of lung cancer molecular features in the context of acquired resistance to specific inhibitors; and (3) to highlight emerging data on other cancer hallmarks that may be of interest from a therapeutic perspective in the next future. From bench to bedside, personalized medicine represents a major revolution in the treatment of lung cancer.     

Therapie im Stadium IV des nichtkleinzelligen Lungenkarzinoms mit Treibermutation

Background

Systemic treatment of non-small cell lung cancer (NSCLC) is currently undergoing a paradigmatic change with impressive dynamics. Patients with advanced disease are treated based on the analysis of biomarkers either with immunotherapy, a combination of immunotherapy with chemotherapy or with driver mutation-directed targeted drugs. Treatment of acquired resistance remains a particular challenge. An increasing knowledge of the molecular mechanisms underlying resistance enables the development of more potent inhibitors.

Objective

This review focuses on the state of the art and current developments in targeted therapy of advanced stage NSCLC.

Material and methods

This review is based on the summary and interpretation of publications on preclinical and clinical studies in the field of targeted treatment of advanced NSCLC.

Results and conclusion

Targeted treatments against activating mutations in the EGFR and BRAF genes as well as ALK and ROS1 fusions define the standard first line treatment for approximately 15?% of patients with advanced NSCLC. In retrospective analyses this development has led to a substantially prolonged overall survival in these subgroups. Targeted therapies against further aberrations are in clinical evaluation and a targeted treatment is currently available for approximately 30% of patients. Next generation inhibitors are characterized by a high effectiveness against tumors with acquired resistance to tyrosine kinase inhibitors (TKI) and improved tolerability and are increasingly being used as first line treatment. In order to understand the molecular causes and to select the most effective treatment, rebiopsies play a special role in resistance.

     

ALK‐positive non–small cell lung cancer: Mechanisms of resistance and emerging treatment options

Targeted therapy has emerged as an effective treatment option for certain molecular subsets of advanced stage non–small cell lung cancer (NSCLC). The discovery of the echinoderm microtubule‐associated protein like 4–anaplastic lymphoma kinase (EML4‐ALK) translocation as an oncogenic driver has led to the development of novel therapies with activity in vitro and in the clinic. The first‐in‐class tyrosine kinase inhibitor crizotinib is effective against ALK‐positive NSCLC and is currently used as first‐line or salvage therapy in the setting of advanced disease. However, resistance inevitably develops through a variety of mechanisms, including point mutations affecting the fusion protein, activation of bypass signaling pathways, copy number gain of ALK, and other means. Increased understanding of these pathways is essential for tailoring treatment choices to improve outcomes and minimize toxicities. Potent second‐generation ALK inhibitors currently in trials are producing encouraging results in ALK‐positive NSCLC, even in patients with acquired resistance to crizotinib. The success in identifying the ALK translocations and rapidly developing targeted drugs to exploit it paves the way for a better understanding of NSCLC biology and the quest to provide effective, personalized treatment for lung cancer patients. Cancer 2014;120:2392–2402. © 2014 American Cancer Society.     

Actionability of on-target ALK Resistance Mutations in Patients With Non-Small Cell Lung Cancer: Local Experience and Review of the Literature

IntroductionNon-small cell lung cancer (NSCLC) patients with Anaplastic Lymphoma Kinase (ALK) gene fusions respond well to ALK inhibitors but commonly develop on-target resistance mutations. The objective of this study is to collect clinical evidence for subsequent treatment with ALK inhibitors.Patients and MethodsLocal experience with on-target ALK resistance mutations and review of the literature identified 387 patients with ALK inhibitor resistance mutations. Clinical benefit of mutation-inhibitor combinations was assessed based on reported response, progression-free survival and duration of treatment. Furthermore, this clinical evidence was compared to previously reported in vitro sensitivity of mutations to the inhibitors.ResultsOf the pooled population of 387 patients in this analysis, 239 (62%) received at least 1 additional line of ALK inhibition after developing on-target resistance to ALK inhibitor therapy. Clinical benefit was reported for 177 (68%) patients, but differed for each mutation-inhibitor combination. Agreement between in vitro predicted sensitivity of 6 published models and observed clinical benefit ranged from 69% to 89%. The observed clinical evidence for highest probability of response in the context of specific on-target ALK inhibitor resistance mutations is presented.ConclusionMolecular diagnostics performed on tissue samples that are refractive to ALK inhibitor therapy can reveal new options for targeted therapy for NSCLC patients. Our comprehensive overview of clinical evidence of drug actionability of ALK on-target resistance mechanisms may serve as a practical guide to select the most optimal drug for individual patients.     

Real-World Clinical Outcomes after Genomic Profiling of Circulating Tumor DNA in Patients with Previously Treated Advanced Non-Small Cell Lung Cancer

Comprehensive genomic profiling for advanced non-small cell lung cancer (NSCLC) can identify patients for molecularly targeted therapies that improve clinical outcomes. We analyzed data from 3084 patients (median age 65 years, 72.9% with adenocarcinoma) with advanced NSCLC registered in a real-world healthcare claims database (GuardantINFORM^TM, Guardant Health) who underwent next-generation sequencing (NGS)-based circulating tumor DNA (ctDNA) testing (Guardant360^®, Guardant Health) after first-line therapy (28.0% with agents targeted against genomic alterations). ctDNA was detected in 2771 samples (89.9%), of which 41.9% harbored actionable alterations, most commonly EGFR (epidermal growth factor receptor) mutations (29.7%). Actionable alterations were detected in 26.7% of patients (534/2001) previously treated with non-targeted agents. Emerging potentially targetable mutations were found in 40.1% (309/770) of patients previously treated with targeted therapies. Among patients with qualifying alterations detected by ctDNA testing, the time to treatment discontinuation (median 8.8 vs. 4.2 months; hazard ratio 1.97, p < 0.001) and overall survival (median 36.1 vs. 16.6 months; hazard ratio 2.08, p < 0.001) were longer for those who received matched second-line therapy versus unmatched second-line therapy. In real-world practice, results of a blood-based NGS assay prior to second-line treatment inform therapeutic decisions that can improve clinical outcomes for patients with advanced NSCLC.     

Duration of Targeted Therapy in Patients With Advanced Non–small-cell Lung Cancer Identified by Circulating Tumor DNA Analysis

BackgroundOutcomes of therapy targeting molecular driver alterations detected in advanced non–small-cell lung (NSCLC) using circulating tumor DNA (ctDNA) have not been widely reported in patients who are targeted therapy-naive.Patients and MethodsWe performed a multicenter retrospective review of patients with unresectable stage IIIB to IV NSCLC who received matched therapy after a targetable driver alteration was identified using a commercial ctDNA assay through usual clinical care. Eligible patients must not have received targeted therapy prior to ctDNA testing (prior chemotherapy or immunotherapy was permitted). Kaplan-Meier analysis was used to estimate the median duration of targeted therapy. Patients still on targeted therapy were censored at last follow-up.ResultsSeventy-six patients met inclusion criteria. The median age of diagnosis of NSCLC was 64.5 years (range, 31-87 years), 67% were female, 74% were never-smokers, and 97% had adenocarcinoma histology. Twenty-one (28%) patients received systemic treatment prior to targeted therapy, including chemotherapy (n = 17), immunotherapy (n = 5), and/or a biologic (n = 4). Thirty-three (43%) patients remain on targeted therapy at the time of data analysis. The median time on targeted therapy was similar to what has been reported for tissue-detected oncogenic driver mutations in the targeted therapy-naive setting.ConclusionsPatients with ctDNA-detected drivers had durable time on targeted therapy. These treatment outcomes data compliment previous studies that have shown enhanced targetable biomarker discovery rates and high tissue concordance of ctDNA testing when incorporated at initial diagnosis of NSCLC. Identification of NSCLC driver mutations using well-validated ctDNA assays can be used for clinical decision-making and targeted therapy assignment.     

The next generation of epidermal growth factor receptor tyrosine kinase inhibitors in the treatment of lung cancer

The discovery of “driver” genomic alterations in patients with non‐small cell lung cancer (NSCLC) has dramatically changed the field of thoracic oncology in recent years. The best understood of these molecular drivers are those involving the epidermal growth factor receptor (EGFR), which when aberrantly activated are integral to the development of a subset of NSCLC tumors. First‐generation and second‐generation tyrosine kinase inhibitors (TKIs) specific to the activated EGFR have shown significant efficacy and have brought about the era of targeted therapy for NSCLC. The most common resistance mechanism is a threonine‐to‐methionine substitution (T790M) in exon 20 of the EGFR gene. Although the previous standard of care in patients with EGFR‐mutated NSCLC that progressed on initial TKI therapy was chemotherapy, third‐generation EGFR TKIs have now been developed and have yielded promising results for this population of patients with NSCLC. This article reviews the emerging data regarding third‐generation agents in the treatment of patients with advanced NSCLC. Cancer 2015;121:E1–E6. © 2014 American Cancer Society.     

ALK阳性非小细胞肺癌靶向治疗耐药机制及治疗管理的研究进展

目前，肺癌仍是世界上最常见的恶性肿瘤，位居癌症死亡原因的第1位，随着靶向治疗的发展，死亡率已显著降低。间变性淋巴瘤激酶（anaplastic lymphoma kinase，ALK）作为对治疗有显著反应的非小细胞肺癌（non-small cell lung carcinoma，NSCLC）基因型，发展至今已有三代针对其靶位的间变性淋巴瘤激酶酪氨酸激酶抑制剂（anaplastic lymphoma kinase-tyrosine kinase inhibitors，ALK-TKIs），新一代的ALK-TKIs比上一代具有更为广泛的作用位点覆盖范围及更强的药物组织穿透能力。发展前路可观，但仍无法规避耐药问题，随着多种ALK抑制剂应用及联合治疗的选择增多，新的耐药后突变、复合突变以及其他多种耐药机制已逐渐被关注。与此同时，相关早期诊断及预后标志物也被发掘证实。NSCLC耐药机制及检测手段在不断更新，治疗以基于基因依赖性的个体化治疗为主，以期通过对多种耐药方式的介入，使得NSCLC逐渐转变为慢性病。本文归纳介绍了ALK抑制剂应用于NSCLC的现状及耐药机制，耐药后治疗策略及诊断和预后标志物的进展，旨在为ALK阳性NSCLC的诊治及耐药后管理策略提供参考依据。      

New Verse for a Familiar Song: Small Molecule Inhibitors for MET exon 14 Skipping Non-Small Cell Lung Cancer

MET exon 14 skipping alterations (METex14) represent one of the newest discovered driver oncogene alterations for non-small cell lung cancer (NSCLC), which serve to define a distinct elderly patient population. New challenges in detection and treatment have emerged. In the last 15 years, the successes of tumor molecular profiling and therapeutic stratification in patients with advanced-stage disease have made NSCLC a poster child in the era of precision medicine. Each of the oncogenic drivers defines a distinct patient population. The selection of treatments based on oncogenic drivers such as EGFR, ALK, and ROS1, among others, has been transformative in terms of the duration and quality of life for patients with NSCLC receiving effective inhibitors. METex14 have emerged as one of the newest additions of driver oncogenes for NSCLC.     

VEGFR2 blockade augments the effects of tyrosine kinase inhibitors by inhibiting angiogenesis and oncogenic signaling in oncogene-driven non-small-cell lung cancers

Molecular agents targeting the epidermal growth factor receptor (EGFR)-, anaplastic lymphoma kinase (ALK)- or c-ros oncogene 1 (ROS1) alterations have revolutionized the treatment of oncogene-driven non-small-cell lung cancer (NSCLC). However, the emergence of acquired resistance remains a significant challenge, limiting the wider clinical success of these molecular targeted therapies. In this study, we investigated the efficacy of various molecular targeted agents, including erlotinib, alectinib, and crizotinib, combined with anti-vascular endothelial growth factor receptor (VEGFR) 2 therapy. The combination of VEGFR2 blockade with molecular targeted agents enhanced the anti-tumor effects of these agents in xenograft mouse models of EGFR-, ALK-, or ROS1-altered NSCLC. The numbers of CD31-positive blood vessels were significantly lower in the tumors of mice treated with an anti-VEGFR2 antibody combined with molecular targeted agents compared with in those of mice treated with molecular targeted agents alone, implying the antiangiogenic effects of VEGFR2 blockade. Additionally, the combination therapies exerted more potent antiproliferative effects in vitro in EGFR-, ALK-, or ROS1-altered NSCLC cells, implying that VEGFR2 inhibition also has direct anti-tumor effects on cancer cells. Furthermore, VEGFR2 expression was induced following exposure to molecular targeted agents, implying the importance of VEGFR2 signaling in NSCLC patients undergoing molecular targeted therapy. In conclusion, VEGFR2 inhibition enhanced the anti-tumor effects of molecular targeted agents in various oncogene-driven NSCLC models, not only by inhibiting tumor angiogenesis but also by exerting direct antiproliferative effects on cancer cells. Hence, combination therapy with anti-VEGFR2 antibodies and molecular targeted agents could serve as a promising treatment strategy for oncogene-driven NSCLC.     

Successful treatment using apatinib with or without docetaxel in heavily pretreated advanced non-squamous non-small cell lung cancer: A case report and literature review

Although targeted therapy directed toward driver mutations has produced a significant efficacy benefit for patients with non-small cell lung cancer (NSCLC), many patients do not possess mutations associated with the approved targeted drugs. Angiogenic agents play an important role in the therapeutic strategy for advanced NSCLC. Apatinib is a novel tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor-2. A phase II clinical trial demonstrated the survival benefit of apatinib monotherapy in advanced NSCLC. Moreover, addition of anti-angiogenic agents to chemotherapy showed robust efficacy in advanced NSCLC, regardless of tumor histology. Here, we present the case of a heavily pretreated lung adenocarcinoma patient who was treated with apatinib and apatinib continuation plus docetaxel re-challenge. He was negative for several driver genes, including EGFR, ALK, KRAS, ROS1, HER2, RET and BRAF. The previous treatment included platinum-based doublets, pemetrexed monotherapy, docetaxel plus bevacizumab, gefitinib monotherapy, nab-paclitaxel monotherapy, irinotecan plus oxaliplatin and radiotherapy. He obtained a partial response after both apatinib monotherapy and apatinib plus docetaxel treatment, with progression-free survival durations of 5 months and 6 months, respectively. This case indicated that apatinib monotherapy or apatinib plus docetaxel might be regarded as a therapeutic option for heavily pretreated patients with advanced non-squamous NSCLC.     

Multiregion sequencing reveals the intratumor heterogeneity of driver mutations in TP53‐driven non‐small cell lung cancer

Intratumor heterogeneity (ITH) in non‐small cell lung cancer (NSCLC) may account for resistance after a period of targeted therapies because drugs destroy only a portion of tumor cells. The recognition of ITH helps identify high‐risk patients to make effective treatment decisions. However, ITH studies are confounded by interpatient heterogeneity in NSCLC and a large amount of passenger mutations. To address these issues, we recruited NSCLC patients carrying TP53 mutations and selected driver mutations within recurrently mutated genes in NSCLC. A total of 12‐paired normal‐tumor tissues were subjected to whole‐genome/whole‐exome sequencing. From these, 367 non‐silent mutations were selected as driver mutations and deeply sequenced in 61 intratumoral microdissections. We identified a universal prevalence of heterogeneity in all 12 tumors, indicating branched evolution. Although TP53 mutations were observed in single biopsy of all 12 tumors, most tumors consist of both TP53 mutated and non‐mutated cells in separate regions within the same tumor. This suggests the late molecular timing of the acquisition of TP53 mutations; therefore, the detection of TP53 mutations in a single biopsy may simply not reflect the early malignant potential. In addition, we identified regions of loss of heterozygosity surrounding TP53 and CDKN2A mutations in tumor 711, which also exhibited heterogeneity in different regional samples. Because the ITH of driver mutations likely has clinical consequences, further efforts are needed to limit the impact of ITH and to improve therapeutic efficiency, which will benefit NSCLC patients receiving targeted treatments.     

Current Drugs and Drug Targets in Non-Small Cell Lung Cancer: Limitations and Opportunities

Lung cancer is a serious health problem and leading cause of death worldwide due to its high incidenceand mortality. More than 80% of lung cancers feature a non-small cell histology. Over few decades, systemicchemotherapy and surgery are the only treatment options in this type of tumor but due to their limited efficacyand overall poor survival of patients, there is an urge to develop newer therapeutic strategies which circumventthe problems. Enhanced knowledge of translational science and molecular biology have revealed that lung tumorscarry diverse driver gene mutations and adopt different intracellular pathways leading to carcinogenesis. Hence,the development of targeted agents against molecular subgroups harboring critical mutations is an attractiveapproach for therapeutic treatment. Targeted therapies are clearly more preferred nowadays over systemictherapies because they target tumor specific molecules resulting with enhanced activity and reduced toxicityto normal tissues. Thus, this review encompasses comprehensive updates on targeted therapies for the drivermutations in non-small cell lung cancer (NSCLC) and the potential challenges of acquired drug resistance facedi n the field of targeted therapy along with the imminent newer treatment modalities against lung cancer.     

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.