Response of a Novel KANK1::ALK Fusion to Alectinib in an Advanced Lung Adenocarcinoma: A Case Report

Authors:
Quanying Tang Department of Lung Cancer Surgery, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China
Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China

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Tong Li Department of Lung Cancer Surgery, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China
Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China

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Fan Ren Department of Lung Cancer Surgery, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China
Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China

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Xuanguang Li Department of Lung Cancer Surgery, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China
Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China

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WeiBo Cao Department of Lung Cancer Surgery, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China
Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China

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Haochuan Yu Department of Lung Cancer Surgery, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China
Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China

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Fuling Mao Department of Lung Cancer Surgery, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China
Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China

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Cancan Cao Department of Lung Cancer Surgery, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China
Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China

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Lingling Zu Department of Lung Cancer Surgery, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China
Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China

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Song Xu Department of Lung Cancer Surgery, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China
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More than 90 distinct fusion partners of ALK rearrangement have been identified. Different ALK fusions may exhibit different sensitivities to ALK tyrosine kinase inhibitors. The emergence of rare fusions poses significant challenges to targeted therapies. This study aimed to investigate the response of KANK1::ALK fusion to alectinib in an advanced lung adenocarcinoma. A novel KANK1::ALK fusion was identified by next-generation sequencing (NGS) and Ventana immunohistochemistry assessments. A 73-year-old woman who had never smoked was admitted with hemoptysis in May 2020. PET/CT revealed a nodule in the left upper lobe, with bilateral pulmonary and multiple lymph node metastases. The upper lobe nodule of the left lung was diagnosed as adenocarcinoma through bronchofiberscopy biopsy, resulting in a clinical diagnosis of stage IVA (cT1c,N3,M1a). Because the biopsy tissue was insufficient for NGS analysis, a blood-based genetic analysis was performed, revealing the presence of KRAS p.Q61R mutations. The patient received carboplatin and pemetrexed with pembrolizumab as first-line therapy, followed by maintenance therapy of pembrolizumab monotherapy. Although the tumor initially showed significant shrinkage, it unfortunately progressed further after 11 months. Subsequently, the patient was given carboplatin and pemetrexed with pembrolizumab again, but the tumor progression continued. An NGS using a rebiopsy of the left upper lobe tumor suggested a KANK1::ALK fusion. Alectinib was prescribed in January 2022, and a durable partial response was observed after 18 months. ALK rearrangements were observed in the broader spectrum of lung cancers. This study provided a potential treatment option for patients with KANK1::ALK fusions. Further studies are needed to understand the function of these fusions.

ALK gene rearrangement is found in approximately 4% of patients with lung cancer, with the most frequent ALK rearrangement being EML4::ALK.1 Patients with ALK-positive lung cancer can achieve remarkable effects from ALK tyrosine kinase inhibitors (TKIs), including crizotinib, alectinib, ceritinib, brigatinib, and lorlatinib.26 Alectinib is considered the first-line treatment for patients with metastatic ALK-positive non–small cell lung cancer (NSCLC).7 It is noteworthy that >90 ALK fusion partners have been reported, and different ALK fusions exhibit distinct responses to ALK TKIs.8 This study was novel in reporting the detection of KANK1::ALK fusion by next-generation sequencing (NGS) in a patient with lung adenocarcinoma.

The study was approved by the ethics committee of Tianjin Medical University General Hospital. Written informed consent was obtained from the patient to publish case details and images.

Case Presentation

In May 2020, a 73-year-old woman who had never smoked was admitted to Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital with hemoptysis. The treatment flowchart for this patient is depicted in Figure 1. Chest CT revealed a soft tissue density nodular shadow in the upper lobe of the left lung, multiple suspicious metastatic nodules in the middle lobe and the lower lobe of the right lung, and enlarged mediastinal lymph nodes. MRI of the head and abdominal CT revealed no abnormalities. PET/CT revealed a hypermetabolic nodule in the left upper lobe, as well as bilateral pulmonary and multiple lymph node metastases. The bronchoscopic biopsy confirmed adenocarcinoma in the upper lobe nodule of the left lung, leading to a clinical diagnosis of stage IVA disease (cT1c,N3,M1a). Immunohistochemical stains were positive for TTF-1, CK7, NapsinA, p63, and CK5/6, but negative for p40, CD56, CgA, and Syn. The Ki-67 index was approximately 30% (see Figure S1 in the supplemental materials, available online with this article). The patient refused a rebiopsy of lung tumor, and the remaining biopsy tissue was insufficient for immunohistochemistry and NGS analysis. Therefore, a blood-based 420-gene NGS (depth 10,000×; Illumina, YinFeng Gene Technology Co., Ltd.) was conducted, revealing the presence of a KRAS p.Q61R mutation (0.6%).

Figure 1.
Figure 1.

Clinical treatment history and imaging data of the patient. May 2020 is when the KRAS mutation was detected, and January 2022 is when the KANK1::ALK fusion was detected.

Abbreviations: NGS, next-generation sequencing; PD, progressive disease; PFS, progression-free survival; PR, partial response.

Citation: Journal of the National Comprehensive Cancer Network 22, 2; 10.6004/jnccn.2023.7107

The patient was then treated with pemetrexed (500 mg/m2 intravenously on day 1 every 3 weeks) and carboplatin (area under the plasma concentration-time curve, 5 mg/mL per min intravenously on day 1 every 3 weeks) in combination with pembrolizumab (200 mg/bodyweight intravenously on day 1 every 3 weeks). An almost complete response was achieved after 5 treatment cycles, followed by maintenance therapy of pembrolizumab monotherapy. However, the tumor relapsed after 11 months. The patient was subsequently treated with carboplatin and pemetrexed with pembrolizumab, but the tumor continued to progress further. A rebiopsy of the left upper lobe tumor was performed, revealing the presence of a KANK1::ALK fusion (12.58%) through NGS analysis (206-gene panel, depth 1,200×; MGISEQ-2000, BGI Genomics) (Figure 2A), which was validated by Ventana immunohistochemical staining of ALK (see Supplementary Figure S2B). Alectinib was prescribed at 600 mg orally twice daily beginning January 2022, and a rapid clinical response was observed. As of the time of writing, a continuous partial response (PR) had been noted for >18 months.

Figure 2.
Figure 2.

NGS analysis of genomic DNA identified a fusion variant of KANK1 intron 3 with ALK intron 19. (A) Paired-end sequencing data from tumor tissue samples indicated somatic interchromosomal KANK1::ALK fusion as demonstrated by Integrative Genomics Viewer program (Broad Institute; https://igv.org/app). (B) Diagram depicting the KANK1::ALK fusion (K3::A20).

Abbreviations: bp, base pairs; cc, coiled coil domain; Chr, chromosome; NGS, next-generation sequencing.

Citation: Journal of the National Comprehensive Cancer Network 22, 2; 10.6004/jnccn.2023.7107

Discussion

This study was novel in reporting the case of a patient with alectinib-responsive lung adenocarcinoma having a KANK1::ALK fusion. The ALEX study recommends alectinib as the first-line treatment in patients with NSCLC having advanced ALK positivity.9 However, patients with NSCLC having different ALK fusions respond to ALK TKIs differently.8,10 Our study detected the KANK1::ALK fusion, which represented a translocation between KANK1 exons 1–3 on chromosome 9 and ALK exons 20–29 on chromosome 2. It retained the N-terminal coiled-coil domains of KANK1 and the intracellular ALK region containing the tyrosine kinase domain (Figure 2B). Additionally, the Ventana ALK (D5F3) CDx IHC assay confirmed ALK protein expression. Previous reports11 have suggested that KANK1, a tumor suppressor gene, can mediate paclitaxel resistance in lung adenocarcinoma A549 cells. In addition, a previous study also reported a pancreatic neuroendocrine carcinoma patient with a KANK1::ALK fusion who exhibited a rapid and profound response to the ALK inhibitor lorlatinib.12 Like our case, the ALK protein tyrosine kinase domain located between exons 20 and 28 is expected to be retained in the fusion product. ALK fusion resulted in the production of oncogenic ALK tyrosine kinase, which activated several downstream signaling pathways.13 This led to tumorigenesis due to uncontrolled cell proliferation. The growth of cancer cells with ALK-positive signals was inhibited by ALK TKIs, which blocked the abnormal ALK signaling pathway. The patient experienced a significant PR after treatment with alectinib, and progression-free survival exceeded 18 months. Therefore, the novel KANK1::ALK fusion was sensitive to alectinib in lung adenocarcinoma. Due to the small amount of tumor tissue, it was impossible to perform a primary culture of the tumor cell or establish a PDX/CDX model; therefore, a lack of functional validation of the KANK1::ALK fusion is a limitation of our study.

Immunotherapy produces a poor response compared with targeted therapies for advanced NSCLC harboring driver mutations such as EGFR or ALK mutations.14 PD-1/PD-L1 inhibitors, however, are more effective in patients with KRAS mutations than in those with wild-type KRAS.15 The findings revealed that KRAS mutations led to a tumor microenvironment that was inflammatory and immunogenic, resulting in a superior response to PD-1 inhibitors in patients with KRAS mutations.15,16 However, not all patients with KRAS mutations benefit from anti–PD-1 immunotherapy. Previous articles17 have mentioned different immunotherapy benefits for different KRAS mutation subtypes. For example, a recent study18 elucidated the molecular mechanisms by which KRAS G12D mutations drive immunosuppression and enhanced resistance to immune checkpoint inhibitors in NSCLC. At the same time, the results also suggest that immune checkpoint inhibitors combined with chemotherapy may be more effective in patients with NSCLC with KRAS G12D mutation. However, how NSCLC with KRAS p.Q61R mutation responded to immunotherapy was still not clear. KRAS p.Q61R mutations were detected in the patient. Because no positive driver gene mutations were detected by the blood-based NGS, we prescribed pemetrexed and carboplatin with pembrolizumab for the patient. Due to significant grade 3 leukopenia during maintenance therapy, the patient was treated with pembrolizumab monotherapy. The tumor exhibited a significant response after 5 cycles of chemoimmunotherapy but further relapsed after 11 months. An NGS using a rebiopsy of the left upper lobe tumor suggested a KANK1::ALK fusion. Multiplex immunostaining (GeneCast Biotechnology) was performed using the tumor tissue of prior and post immunochemotherapy to explore the characterization of immunochemotherapy resistance. The staining data (see Supplementary Figure S2C, D) demonstrated that the proportion of M2 macrophages increased after the immunochemotherapy resistance. The number of CD4+ FOXP3+ cells increased, although without statistical significance. Therefore, these changes suggest that the tumor microenvironment (TME) turns into a more immunosuppressive state. The reason is probably due to the redistribution of immune and inflammatory cells and the ALK-mutant tumor cell expansion after immunochemotherapy. The exact underlying mechanisms need to be further explored.

We retrospectively performed Ventana immunohistochemical staining of ALK on the tumor tissue from a bronchoscopic biopsy, and it also showed positive ALK expression (see Supplementary Figure S3). This patient may have KRAS and ALK co-mutations in the baseline stage, probably due to the tumor heterogeneity. We hypothesized that only KRAS mutation was detected at the baseline due to the limited sequencing depth from the blood and less quantity of ALK-mutated cells. Previous studies19 revealed primary resistance to ALK inhibitors due to KRAS mutation, and platinum-containing chemotherapy should be used as first-line therapy for ALK/KRAS double-mutant NSCLC. Therefore, the use of chemoimmunotherapy for first-line treatment in this study is also reasonable. Moreover, KRAS and ALK mutations might occur exclusively in NSCLC.20 At first, the cell population with KRAS mutation might occupy most of the tumor. However, KRAS-mutated tumors were significantly killed after the immunotherapy. Also, the tumor cells with ALK mutation eventually expanded faster and dominated, forming an immunosuppressive microenvironment. This was also consistent with findings from our previous study,21 suggesting that patients with ALK-positive NSCLC more likely had immunosuppressive TME than those with KRAS-positive NSCLC.

Conclusions

This study was novel in reporting the case of a patient with lung adenocarcinoma harboring a KANK1::ALK (K3::A20) fusion. Data analysis in this study confirmed that the ALK TKI alectinib was effective in this rare type of NSCLC with fusion. Moreover, the tumor immunologic microenvironment was also explored. ALK arrangement types can be expanded and treatment regimens for lung adenocarcinomas can be explored based on the findings of this study.

Acknowledgments

The authors thank the patient and her family.

References

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    Sun K, Nie L, Nong L, et al. Primary resistance to alectinib in a patient with STRN-ALK-positive non-small cell lung cancer: a case report. Thorac Cancer 2021;12:19271930.

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    Pu J, Shen J, Zhong Z, et al. KANK1 regulates paclitaxel resistance in lung adenocarcinoma A549 cells. Artif Cells Nanomed Biotechnol 2020;48:639647.

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    Dayyani F, Lee W, Houshyar R, et al. Rapid and deep response to lorlatinib in pancreatic high-grade neuroendocrine carcinoma with a treatment emergent novel KANK1-ALK fusion. JCO Precis Oncol 2023;7:e2200230.

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    Golding B, Luu A, Jones R, et al. The function and therapeutic targeting of anaplastic lymphoma kinase (ALK) in non-small cell lung cancer (NSCLC). Mol Cancer 2018;17:52.

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    Mazieres J, Drilon A, Lusque A, et al. Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET registry. Ann Oncol 2019;30:13211328.

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    Liu C, Zheng S, Wang Z, et al. KRAS-G12D mutation drives immune suppression and the primary resistance of anti-PD-1/PD-L1 immunotherapy in non-small cell lung cancer. Cancer Commun (Lond) 2022;42:828847.

    • PubMed
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    • Export Citation
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    Schmid S, Gautschi O, Rothschild S, et al. Clinical outcome of ALK-positive non-small cell lung cancer (NSCLC) patients with de novo EGFR or KRAS co-mutations receiving tyrosine kinase inhibitors (TKIs). J Thorac Oncol 2017;12:681688.

    • PubMed
    • Search Google Scholar
    • Export Citation
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    Gainor JF, Varghese AM, Ou SHI, et al. ALK rearrangements are mutually exclusive with mutations in EGFR or KRAS: an analysis of 1,683 patients with non-small cell lung cancer. Clin Cancer Res 2013;19:42734281.

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    • Search Google Scholar
    • Export Citation
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    • Search Google Scholar
    • Export Citation

Submitted July 3, 2023; final revision received October 14, 2023; accepted for publication November 8, 2023. Published online February 15, 2024.

Disclosures: The authors have disclosed that they have no financial interests, arrangements, affiliations, or commercial interests with the manufacturers of any products discussed in this article or their competitors.

Funding: Research reported in this publication was supported by the National Natural Science Foundation of China (82172776; S. Xu), National Key Clinical Specialty Discipline Construction Program of China (TJYXZDXK-061B; S. Xu), Tianjin Postgraduate Research and Innovation Project (2022SKYZ122; Q. Tang), and Diversified Input Project of Tianjin National Science Foundation (21JCYBJC01770; S. Xu).

Supplementary material: Supplementary material associated with this article is available online at https://doi.org/10.6004/jnccn.2023.7107. The supplementary material has been supplied by the author(s) and appears in its originally submitted form. It has not been edited or vetted by JNCCN. All contents and opinions are solely those of the author. Any comments or questions related to the supplementary materials should be directed to the corresponding author.

Correspondence: Song Xu, MD, PhD, Department of Lung Cancer Surgery, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, 154 Anshan Road, Heping, Tianjin 300052, P.R. China. Email: xusong198@hotmail.com

Supplementary Materials

  • Collapse
  • Expand
  • Figure 1.

    Clinical treatment history and imaging data of the patient. May 2020 is when the KRAS mutation was detected, and January 2022 is when the KANK1::ALK fusion was detected.

    Abbreviations: NGS, next-generation sequencing; PD, progressive disease; PFS, progression-free survival; PR, partial response.

  • Figure 2.

    NGS analysis of genomic DNA identified a fusion variant of KANK1 intron 3 with ALK intron 19. (A) Paired-end sequencing data from tumor tissue samples indicated somatic interchromosomal KANK1::ALK fusion as demonstrated by Integrative Genomics Viewer program (Broad Institute; https://igv.org/app). (B) Diagram depicting the KANK1::ALK fusion (K3::A20).

    Abbreviations: bp, base pairs; cc, coiled coil domain; Chr, chromosome; NGS, next-generation sequencing.

  • 1.

    Solomon BJ, Varella-Garcia M, Camidge DR. ALK gene rearrangements: a new therapeutic target in a molecularly defined subset of non-small cell lung cancer. J Thorac Oncol 2009;4:14501454.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2.

    Solomon BJ, Mok T, Kim DW, et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med 2014;371:21672177.

  • 3.

    Gettinger SN, Bazhenova LA, Langer CJ, et al. Activity and safety of brigatinib in ALK-rearranged non-small-cell lung cancer and other malignancies: a single-arm, open-label, phase 1/2 trial. Lancet Oncol 2016;17:16831696.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4.

    Hida T, Nokihara H, Kondo M, et al. Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): an open-label, randomised phase 3 trial. Lancet 2017;390:2939.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5.

    Shaw AT, Felip E, Bauer TM, et al. Lorlatinib in non-small-cell lung cancer with ALK or ROS1 rearrangement: an international, multicentre, open-label, single-arm first-in-man phase 1 trial. Lancet Oncol 2017;18:15901599.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6.

    Soria JC, Tan DS, Chiari R, et al. First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study. Lancet 2017;389:917929.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7.

    Peters S, Camidge DR, Shaw AT, et al. Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer. N Engl J Med 2017;377:829838.

  • 8.

    Ou SHI, Zhu VW, Nagasaka M. Catalog of 5′ fusion partners in ALK-positive NSCLC circa 2020. JTO Clin Res Rep 2020;1:100015.

  • 9.

    Mok T, Camidge DR, Gadgeel SM, et al. Updated overall survival and final progression-free survival data for patients with treatment-naive advanced ALK-positive non-small-cell lung cancer in the ALEX study. Ann Oncol 2020;31:10561064.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10.

    Sun K, Nie L, Nong L, et al. Primary resistance to alectinib in a patient with STRN-ALK-positive non-small cell lung cancer: a case report. Thorac Cancer 2021;12:19271930.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11.

    Pu J, Shen J, Zhong Z, et al. KANK1 regulates paclitaxel resistance in lung adenocarcinoma A549 cells. Artif Cells Nanomed Biotechnol 2020;48:639647.

  • 12.

    Dayyani F, Lee W, Houshyar R, et al. Rapid and deep response to lorlatinib in pancreatic high-grade neuroendocrine carcinoma with a treatment emergent novel KANK1-ALK fusion. JCO Precis Oncol 2023;7:e2200230.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13.

    Golding B, Luu A, Jones R, et al. The function and therapeutic targeting of anaplastic lymphoma kinase (ALK) in non-small cell lung cancer (NSCLC). Mol Cancer 2018;17:52.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14.

    Mazieres J, Drilon A, Lusque A, et al. Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET registry. Ann Oncol 2019;30:13211328.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15.

    Liu C, Zheng S, Jin R, et al. The superior efficacy of anti-PD-1/PD-L1 immunotherapy in KRAS-mutant non-small cell lung cancer that correlates with an inflammatory phenotype and increased immunogenicity. Cancer Lett 2020;470:95105.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16.

    Lee CK, Man J, Lord S, et al. Clinical and molecular characteristics associated with survival among patients treated with checkpoint inhibitors for advanced non-small cell lung carcinoma: a systematic review and meta-analysis. JAMA Oncol 2018;4:210216.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17.

    Lei L, Wang WX, Yu ZY, et al. A real-world study in advanced non-small cell lung cancer with KRAS mutations. Transl Oncol 2020;13:329335.

  • 18.

    Liu C, Zheng S, Wang Z, et al. KRAS-G12D mutation drives immune suppression and the primary resistance of anti-PD-1/PD-L1 immunotherapy in non-small cell lung cancer. Cancer Commun (Lond) 2022;42:828847.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19.

    Schmid S, Gautschi O, Rothschild S, et al. Clinical outcome of ALK-positive non-small cell lung cancer (NSCLC) patients with de novo EGFR or KRAS co-mutations receiving tyrosine kinase inhibitors (TKIs). J Thorac Oncol 2017;12:681688.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20.

    Gainor JF, Varghese AM, Ou SHI, et al. ALK rearrangements are mutually exclusive with mutations in EGFR or KRAS: an analysis of 1,683 patients with non-small cell lung cancer. Clin Cancer Res 2013;19:42734281.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21.

    Zhang B, Zeng J, Zhang H, et al. Characteristics of the immune microenvironment and their clinical significance in non-small cell lung cancer patients with ALK-rearranged mutation. Front Immunol 2022;13:974581.

    • PubMed
    • Search Google Scholar
    • Export Citation
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