Good responses to first-line immunotherapy-included treatment in lung squamous carcinoma with rare driver gene mutations: a report of three cases

Introduction

Non-small cell lung cancer (NSCLC) can be divided into adenocarcinoma, lung squamous carcinoma (LUSC) and other tissue types according to pathological features. With the development of precision medicine from the 21^st century, the classification of driver gene mutation-positive or -negative lung cancer has emerged as being critically important to treatment. Generally, these two types of lung cancer show distinct difference in treatment response. Instead of immunotherapy, tyrosine kinase inhibitor (TKI) treatment has been recommended for patients with driver gene mutations such as epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK). Immunotherapy, primarily consisting of immune checkpoint inhibitors, has become the favored therapeutic approach for driver gene-negative NSCLC but was previously considered less efficacious for EGFR or ALK positive NSCLC. However, recent studies indicate that there is a segment of patients with driver gene mutations that may benefit from immunotherapy under certain circumstances. For example, the efficacy of immunotherapy in patients harboring B-Raf (BRAF) V600E or K-Ras (KRAS) mutations may be similar to that in driver gene-negative NSCLC, whereas classical EGFR target mutations including exon 19 deletion (19-Del) or L858R, EGFR 20-insertion (ins), and NSCLC with fusion mutations including ALK, c-ros oncogene 1 (ROS-1), and ret proto-oncogene (RET) may show worse immunotherapy efficacy (1,2). In contrast, studies such as IMpower150 and ORIENT31 reported that even for patients with NSCLC and classical EGFR mutations who were refractory to TKI-targeted therapies, combined treatment modalities such as chemotherapy and immunotherapy with/without anti-angiogenic therapy could still provide a survival benefit (3,4). These findings suggest that the screening of potentially advantageous populations based on clinical or molecular features may allow for some patients with driver gene mutation positive NSCLC to benefit from immunotherapy.

Fewer than 5% patients with LUSC have driver gene mutation, which is significantly lower than that in adenocarcinoma. Several retrospective studies and case reports have suggested that compared to adenocarcinoma, LUSC with driver gene mutations experience significantly less benefit from TKI targeted therapies and have limited second-line treatment options and worse prognosis (5,6). Therefore, it is necessary to identify novel treatment modalities for this population. Patients with LUSC have a significant survival benefit from immunotherapy and gene mutation detection is not required for them. Once EGFR or ALK mutation is confirmed with a patient, TKIs is recommended including LUSC. Therefore, whether LUSC patients with rare driver gene mutations would benefit from immunotherapy-included treatment modalities remains unknown. Recently, there are two case reports focused on immunotherapy for driver gene mutation squamous lung carcinoma. Wei et al. reported a patient with EML4-ALK rearrangement have a good response to immunotherapy (7) and Yang et al. reported a complete response (CR) of an advanced ALK-positive LUSC with anti-PD-1 immunotherapy post ALK-TKIs failure (8). However, due to the extremely low proportion of LUSC patients with driver gene mutations, especially rare EGFR mutations, or ALK fusions, there is an insufficient amount of data regarding the efficacy of immunotherapy in LUSC patients with rare driver gene mutations. We therefore reviewed efficacy of immunotherapy for some LUSC patients with rare EGFR driver mutations or ALK mutations in Lung Cancer Center, West China Hospital, which might provide new directions for optimizing treatment options for this population. We present this article in accordance with the CARE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-469/rc).

Case presentation

Case 1

A 50-year-old non-smoking female arrived at West China Hospital in May 2022 with a cough, hoarseness and blood in the sputum. Chest computed tomography (CT) revealed occupations in the posterior segment of the upper lobe and dorsal segment of the lower lobe of the right lung. Fiberoptic bronchoscopy revealed a bronchial neoplasm in the dorsal segment of the lower lobe of the right lung. The pathological diagnosis was NSCLC with squamous component, T4N0M0 IIIA, tumor proportion score (TPS) and combined positive score (CPS) of PD-L1 (22C3) were 90% and 100%, respectively. As the tumor was potentially resectable, neoadjuvant immunotherapy-tislelizumab in combination with albumin-paclitaxel and carboplatin were initiated in July 2022, partial response (PR) was achieved in two cycles of treatment. Radical resection was performed, and postoperative pathology showed CR in the primary site and no metastases in the lymph nodes. To further guide the postoperative treatment, the patient’s biopsy specimen before immunotherapy was sent for genetic testing, which showed EGFR p.G719S point mutation with 24.9% mutation abundance, EGFR p.S768I point mutation with 24.6% mutation abundance, along with TP53 p.S183* mutation with a 7.2% mutation abundance and low tumor mutation burden (TMB, 0.0 Muts/Mb). As the patient had achieved a postoperative pathological CR, there was no exact evidence of benefit for either postoperative adjuvant immunotherapy or chemotherapy; therefore, she was continued on two cycles of immunochemotherapy after the surgery. No recurrence or metastasis was observed through systematic imaging performed in March 2025, consistent with a postoperative disease-free survival (DFS) exceeding 30 months and an overall survival (OS) exceeding 34 months (Figure 1A).

Figure 1 Treatment of patients with LUSC and rare driver gene mutations. Treatment history and imaging changes of lung cancer in the (A) first patient, (B) second patient, and (C) third patient (the red arrows indicate tumor lesions of patients). CT, computed tomography; LUSC, lung squamous carcinoma; NGS, next-generation sequencing; pCR, pathological complete response; PD, progressive disease; PR, partial response.

Case 2

A 65-year-old non-smoking female had intermittent cough and hemoptysis, which lasted for 2 months and her CT of chest in February 2019 found cystic occupancy in the lower lobe of the left lung and a percutaneous lung puncture suggested squamous carcinoma. Salvage surgery was performed in April 2019 due to CT imaging showing central necrotizing cystic occupancy with a risk of breaking through the pericardium, leading to pyothorax and pleural dissemination. Intraoperatively, multiple implantation nodules in the wall pleura and a huge mass in the lower lobe of the left lung, measuring approximately 10 cm × 9 cm × 8 cm, were observed; therefore, palliative resection was performed. Postoperative pathology suggested a middle-differentiated squamous carcinoma (keratinized type) in the lower lobe of the left lung, with involvement in the pleural implantation nodes. One month after surgery, the patient rapidly developed metastases to both lungs, the spleen, and ribs, and the postoperative stage was T4N0M1c, IVB. Genetic testing was applied to develop next treatment strategy and the result revealed EGFR exon 20ins in S768_D770dupSVD with a 35.13% mutation abundance, EGFR amplification (copy number:3.39) and TP53 mutation with a 20.26% mutation abundance with a moderate TMB (5.092 Muts/Mb), and TPS of PD-L1 (22C3) was 5%. Pembrolizumab was administered in combination with liposomal paclitaxel and lobaplatin. The patient’s symptoms rapidly resolved, and a PR was achieved. Consequently, therapy was switched to maintenance with pembrolizumab, during which the patient’s tumor continued to shrink to clinical CR. In the immune-maintenance phase, the patient developed infectious pneumonia and grade III thrombocytopenia, inflammation gradually organized after treatment, but thrombocytopenia has been always existing. Immunotherapy was discontinued in August 2021 after 2 years. In the follow-up of March 2025, the patient remains good Eastern Cooperative Oncology Group (ECOG) performance status and relapse-free, refused re-examination by CT scan, with a progression-free survival (PFS) of >68 months and an OS of >70 months (Figure 1B).

Case 3

A 28-year-old non-smoking woman arrived at clinic in June 2022 complaining of a recurrent cough. Comprehensive imaging revealed lesions in the right lower lobe of lung with multiple lymphadenopathy in the hilar, mediastinal, and right supraclavicular regions. Other occupations in right intrapulmonary, right pleural and bilateral adnexal, considered to be metastases. A lung puncture biopsy showed squamous cell carcinoma with a PD-L1 (22C3) TPS of 5%, and the stage was T4N3M1c, IVB. Treatment, including PD-1 inhibitor tislelizumab with albumin-paclitaxel and carboplatin, was initiated in July 2022. After two cycles, all lesions were significantly reduced and achieved PR. Six cycles later, positron emission tomography (PET)-CT performed and result showed no residual lesions except the primary lesion in the right lower lobe of lung. The patient underwent salvage surgery for right lower lobectomy and systemic lymph node dissection in March 2023. Postoperative pathology suggested moderately differentiated non-keratinizing squamous carcinoma with approximately 70% residual tumor tissue, 20% necrotic tissue and 10% fibrosis and inflammation. No tumor metastasis was observed in all lymph nodes sent for pathological examination. The lymph nodes in groups 7 and 8 showed post-treatment reactions, with no extraperitoneal invasion of the lymph nodes. Considering the high proportion of tumor residual and next-generation sequencing (NGS) was applied and result identified EML4-ALK fusion (exon 6 and exon 20) (V3) with a 8% mutation abundance, TP53 p.G245S mutation in exon7 with a 18.6% mutation abundance, and low TMB (1.92 Muts/Mb). The patient began taking alectinib in May 2023. She achieved a postoperative DFS of >24 months and an OS of >33 months through her last imaging examination in March 2025 (Figure 1C).

The basic clinical information of the three patients is shown in Table 1. A general overview of the treatment is shown in Figure 2.

Figure 2 Treatment and outcomes in the three patients (sorted by survival).

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s), and with the Declaration of Helsinki and its subsequent amendments. Written informed consents were obtained from the patients for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

This case report involves three LUSC patients with rare driver gene mutations who received immunochemotherapy and achieved long-term survival (≥33 months), tentatively suggesting that these patients may benefit from immunochemotherapy.

LUSC occurs with a very low percentage of EGFR or ALK driver gene mutation, which are characterized by a distinct population and clinical features. EGFR mutation is the most common driver gene mutation in NSCLC, occurring in 15–50% of non-squamous NSCLC (9-11); however, the proportion of LUSC patients is exceedingly low. The reported proportion of EGFR exon 19-Del or L858R mutation in squamous carcinoma is approximately 2.97–7.88% (11,12). Rare EGFR mutations occur in significantly low proportions in LUSC, with the frequency of G719X and L861Q mutations ranging from 0.04% to 0.3% and that of 20ins mutation being 0.25% (13). ALK gene fusion accounts for only approximately 0–1.36% of LUSC (14-18). The percentages reported in Lung Cancer in 2019 were 0.17% by fluorescence in situ hybridization (FISH) and 0.55% by NGS (19). Even when tested with surgically resected macroscopic tissue specimens, the percentage of ALK gene fusion positivity is only 2.50% in LUSC (20).

Female, non-smoking, younger age and Asian ethnicity may be traits associated with driver gene mutations in LUSC (12,13). Targeted therapy is less effective for LUSC patients with EGFR or ALK mutations than those mutations in non-squamous NSCLC. Currently, the international guidelines for NSCLC recommend TKIs as the first choice for patients positive for driver gene mutations. However, the efficacy of EGFR-TKI in LUSC varies widely across different cases and retrospective studies but is generally reported to be inferior to that in non-squamous carcinoma. First-generation EGFR-TKIs in LUSC patients with exon 19-Del or L858R (first-line or post-line) yields an objective response rate (ORR) of 28.6%, a median PFS of 4.7 months and a median OS of 10.6 months (13,21). The efficacy of targeted therapy for LUSC patients with rare EGFR mutations has not been extensively reported. In a case report, a patient with LUSC with EGFR G719X achieved a PFS of 15 months with first-line albumin-paclitaxel and carboplatin chemotherapy in combination with afatinib (22). The efficacy of EGFR-TKIs in LUSC patients with EGFR exon 20ins has not been reported due to its extremely low incidence. However, based on historical data, EGFR exon 20ins may be associated with poor response to both first- and second-generation EGFR-TKIs. Data from recent clinical studies on several new agents targeting exon 20ins, such as amivantamab, mobocertinib and sunvozertinib have not reported efficacy exceeding those of classical EGFR-TKIs in NSCLC patients with EGFR exon 19-Del or L858R point mutation (23-25). Wang et al. proposed that the molecular mechanism underlying the significantly worse efficacy of EGFR-TKIs in LUSC may be the simultaneous activation of the bypassed BMP-BMPR-SMAD1/5-p7056K and PI3K-AKT-mTOR pathways in LUSC tumor cells, which reduces the inhibitory effect of EGFR-TKIs on the EGFR signaling pathway (26).

Data regarding the efficacy of ALK-TKIs in ALK-positive LUSC is mostly based on case series reports. Meng et al. reported on 20 cases of ALK-positive LUSC treated with crizotinib (first-line + back-line), reporting an ORR of 55%, a disease control rate of 75% and duration of response of 6.4±4.4 months (27). Case reports have also described the use of the second-generation ALK-TKI alectinib, which may be superior to crizotinib in the treatment of ALK-positive LUSC, providing a PFS up to 9.5 months (28-30). However, other study have reported poor treatment efficacy for alectinib in ALK-positive LUSC (31). The reported efficacy of ALK-TKIs for ALK-positive LUSC is much lower than that for the ALK-positive lung adenocarcinoma [median PFS: 11 months in crizotinib vs. 41.6 months in alectinib (32)]. One study analyzing tumor cells from ALK-positive LUSC observed chromosomal instability in the chromatin of tumor cells. This differs from the molecular manifestations of ALK-positive lung adenocarcinoma cells, which show chromosomally stable genomic profiles unless a TP53 mutation is present. This suggests that the molecular mechanism of tumorigenesis differs between LUSC and adenocarcinoma, despite the fusion mutation type being the same. This may explain the varied responses to TKIs between patients with LUSC and lung adenocarcinoma (33).

Previous studies reported that median ORR of immunotherapy was 33.3% and 50% for NSCLC (including adenocarcinoma and LUSC) patients with MET 14 skipping mutation or EGFR/HER2 exon 20ins, respectively (34,35), which is worse than driver gene mutation negative NSCLC. Immunotherapy is a major strategy for LUSC, but the efficacy of immunotherapy for rare driver gene mutation positive LUSC haven’t been reported. We encountered three cases of LUSC with rare EGFR gene mutations or ALK fusion mutations that showed impressive responses to immunotherapy-included treatment. Case 1 achieved pathological CR after two cycles of immunochemotherapy, followed by a DFS of at least 30 months. Case 2 underwent four cycles of immunochemotherapy and quickly achieved PR during treatment, which was followed by 2 years of immunotherapy. In case 3, all metastatic lesions, but not the primary lesion, quickly reached CR after 2 cycles of immunochemotherapy and remained absent in the subsequent 8 months until salvage surgery was performed; meanwhile, the primary lesion gradually grew soon after PR was achieved. This phenomenon constitutes a type of atypical response known as dissociated response for immunotherapy (36,37), in which the patient partially benefits from immunotherapy (38-40). The efficacy of immunochemotherapy in these cases was superior to that reported in the literature for advanced-stage LUSC treated with chemotherapy alone (typically mPFS of 5–6 months and mOS of approximately 12 months) (41,42), suggesting that immunotherapy may at least partly contribute to the efficacy of combination treatment regimens. Regarding the molecular mechanisms, LUSC patients with driver gene mutation have stronger tumor heterogeneity than do those with adenocarcinoma, suggesting them as a population that could benefit from immunotherapy (43,44). Except case 2 had thrombocytopenia, which was considered to be related to immunotherapy, another two patients had no immune-related adverse effects (irAEs), even the most common endocrine irAEs. But we need to pay attention to irAEs management of these driver gene mutation patients in the future.

Another shared characteristic of these three patients was that they underwent salvage or radical resection during the course of treatment, suggesting a potential role for surgery in this patient population. Recently, there have been small-sample retrospective studies conducted that highly select salvage surgical treatment may provide a survival benefit in certain advanced-stage patients with oncologic emergencies such as lung abscess or abscess with hemoptysis (45). Some studies also indicate that surgery of residual primary, metastatic or recurrent foci, either after targeted therapy or immunotherapy is safe, feasible and beneficial to prolonging survival (45-48). Surgery can also provide a biomass specimen of the tumor for further analysis of the pathological type and molecular characteristics, which can occasionally result in a decisive therapeutic turnaround.

This study involved several limitations which should be acknowledged. Firstly, as only three patients were included in this case report, statistical analysis was not possible, and bias was inevitable. Secondly, the three cases harbored three different types of driver gene mutations and not the same mutation type. However, it is difficult to collect individual cases undergoing immunotherapy due to the extremely low number of LUSC cases with driver gene mutation, and oncologists hold different views regarding the use of immunotherapy for this type of patients. In the future, we will go on our work to collect more patients and explore biomarker for efficacy of immunotherapy in driver gene mutation positive LUSC.

Conclusions

This case report on three women diagnosed with stage IIIA–IVB LUSC or with squamous carcinoma components and rare driver mutations (EGFR exon 18 point mutation G719X/S768I, EGFR exon 20ins, or EML4-ALK fusion) confirmed by genetic testing. The finding of cases enlighten that further prospective clinical cohort studies to validate the efficacy of this regimen is necessary, and basic experimental studies are also important to clarify the related mechanisms.

Acknowledgments

The authors would like to acknowledge the reviewers for their helpful comments on this paper.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-469/rc

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-469/prf

Funding: This work was supported by the 1•3•5 Project for Disciplines of Excellence–Clinical Research Incubation Project, West China Hospital, Sichuan University (No. 2023HXFH021).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-469/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s), and with the Declaration of Helsinki and its subsequent amendments. Written informed consents were obtained from the patients for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Negrao MV, Skoulidis F, Montesion M, et al. Oncogene-specific differences in tumor mutational burden, PD-L1 expression, and outcomes from immunotherapy in non-small cell lung cancer. J Immunother Cancer 2021;9:e002891. [Crossref] [PubMed]
2. Seegobin K, Majeed U, Wiest N, et al. Immunotherapy in Non-Small Cell Lung Cancer With Actionable Mutations Other Than EGFR. Front Oncol 2021;11:750657. [Crossref] [PubMed]
3. Socinski MA, Jotte RM, Cappuzzo F, et al. Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC. N Engl J Med 2018;378:2288-301. [Crossref] [PubMed]
4. Lu S, Wu L, Jian H, et al. Sintilimab plus bevacizumab biosimilar IBI305 and chemotherapy for patients with EGFR-mutated non-squamous non-small-cell lung cancer who progressed on EGFR tyrosine-kinase inhibitor therapy (ORIENT-31): first interim results from a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol 2022;23:1167-79. [Crossref] [PubMed]
5. Zhuang J, Yu Y, Li Z, et al. Efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in targeted therapy of lung squamous cell carcinoma patients with EGFR mutation: a pooled analysis. Oncotarget 2017;8:53675-83. [Crossref] [PubMed]
6. Jin R, Peng L, Shou J, et al. EGFR-Mutated Squamous Cell Lung Cancer and Its Association With Outcomes. Front Oncol 2021;11:680804. [Crossref] [PubMed]
7. Wei J, Sun W, Zeng X, et al. Efficacy analysis of ALK inhibitors for treating lung squamous carcinoma patients harboring ALK rearrangement. J Thorac Dis 2024;16:4146-54. [Crossref] [PubMed]
8. Yang C, Zeng R, Zha Y, et al. Case report: Clinical complete response in advanced ALK-positive lung squamous cell carcinoma: a case study of successful anti-PD-1 immunotherapy post ALK-TKIs failure. Front Immunol 2024;15:1360671. [Crossref] [PubMed]
9. Barlesi F, Mazieres J, Merlio JP, et al. Routine molecular profiling of patients with advanced non-small-cell lung cancer: results of a 1-year nationwide programme of the French Cooperative Thoracic Intergroup (IFCT). Lancet 2016;387:1415-26. [Crossref] [PubMed]
10. Imyanitov EN, Iyevleva AG, Levchenko EV. Molecular testing and targeted therapy for non-small cell lung cancer: Current status and perspectives. Crit Rev Oncol Hematol 2021;157:103194. [Crossref] [PubMed]
11. Shi Y, Au JS, Thongprasert S, et al. A prospective, molecular epidemiology study of EGFR mutations in Asian patients with advanced non-small-cell lung cancer of adenocarcinoma histology (PIONEER). J Thorac Oncol 2014;9:154-62. [Crossref] [PubMed]
12. Gao X, Zhu J, Chen L, et al. Clinical And Imageological Features Of Lung Squamous Cell Carcinoma With EGFR Mutations. Cancer Manag Res 2019;11:9017-24. [Crossref] [PubMed]
13. Zhou S, Wang H, Jiang W, et al. Clinicopathological Characteristics And EGFR-TKIs Efficacies In Lung Squamous Cell Carcinoma Patients Harboring An EGFR Sensitizing Mutation. Onco Targets Ther 2019;12:8863-71. [Crossref] [PubMed]
14. Boland JM, Erdogan S, Vasmatzis G, et al. Anaplastic lymphoma kinase immunoreactivity correlates with ALK gene rearrangement and transcriptional up-regulation in non-small cell lung carcinomas. Hum Pathol 2009;40:1152-8. [Crossref] [PubMed]
15. Takahashi T, Sonobe M, Kobayashi M, et al. Clinicopathologic features of non-small-cell lung cancer with EML4-ALK fusion gene. Ann Surg Oncol 2010;17:889-97. [Crossref] [PubMed]
16. Lindeman NI, Cagle PT, Beasley MB, et al. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. J Mol Diagn 2013;15:415-53. [Crossref] [PubMed]
17. Perez-Moreno P, Brambilla E, Thomas R, et al. Squamous cell carcinoma of the lung: molecular subtypes and therapeutic opportunities. Clin Cancer Res 2012;18:2443-51. [Crossref] [PubMed]
18. Watanabe J, Togo S, Sumiyoshi I, et al. Clinical features of squamous cell lung cancer with anaplastic lymphoma kinase (ALK)-rearrangement: a retrospective analysis and review. Oncotarget 2018;9:24000-13. [Crossref] [PubMed]
19. Wang H, Sun L, Sang Y, et al. A study of ALK-positive pulmonary squamous-cell carcinoma: From diagnostic methodologies to clinical efficacy. Lung Cancer 2019;130:135-42. [Crossref] [PubMed]
20. Caliò A, Nottegar A, Gilioli E, et al. ALK/EML4 fusion gene may be found in pure squamous carcinoma of the lung. J Thorac Oncol 2014;9:729-32. [Crossref] [PubMed]
21. Rekowska A, Rola P, Wójcik-Superczyńska M, et al. Efficacy of Osimertinib in Lung Squamous Cell Carcinoma Patients with EGFR Gene Mutation-Case Report and a Literature Review. Curr Oncol 2022;29:3531-9. [Crossref] [PubMed]
22. Bi H, Ren D, Wu J, et al. Lung squamous cell carcinoma with rare epidermal growth factor receptor mutation G719X: a case report and literature review. Ann Transl Med 2021;9:1805. [Crossref] [PubMed]
23. Park K, Haura EB, Leighl NB, et al. Amivantamab in EGFR Exon 20 Insertion-Mutated Non-Small-Cell Lung Cancer Progressing on Platinum Chemotherapy: Initial Results From the CHRYSALIS Phase I Study. J Clin Oncol 2021;39:3391-402. [Crossref] [PubMed]
24. Zhou C, Ramalingam SS, Kim TM, et al. Treatment Outcomes and Safety of Mobocertinib in Platinum-Pretreated Patients With EGFR Exon 20 Insertion-Positive Metastatic Non-Small Cell Lung Cancer: A Phase 1/2 Open-label Nonrandomized Clinical Trial. JAMA Oncol 2021;7:e214761. [Crossref] [PubMed]
25. Wang M, Fan Y, Sun M, et al. Sunvozertinib for patients in China with platinum-pretreated locally advanced or metastatic non-small-cell lung cancer and EGFR exon 20 insertion mutation (WU-KONG6): single-arm, open-label, multicentre, phase 2 trial. Lancet Respir Med 2024;12:217-24. [Crossref] [PubMed]
26. Wang Z, Shen Z, Li Z, et al. Activation of the BMP-BMPR pathway conferred resistance to EGFR-TKIs in lung squamous cell carcinoma patients with EGFR mutations. Proc Natl Acad Sci U S A 2015;112:9990-5. [Crossref] [PubMed]
27. Meng Q, Dong Y, Tao H, et al. ALK-rearranged squamous cell carcinoma of the lung. Thorac Cancer 2021;12:1106-14. [Crossref] [PubMed]
28. Mamesaya N, Nakashima K, Naito T, et al. ALK-rearranged lung squamous cell carcinoma responding to alectinib: a case report and review of the literature. BMC Cancer 2017;17:471. [Crossref] [PubMed]
29. Shiihara J, Ohyanagi F, Amari H, et al. Dramatic response to alectinib in a patient with ALK-rearranged squamous cell lung cancer. Thorac Cancer 2021;12:2420-3. [Crossref] [PubMed]
30. Sagawa R, Ohba T, Ito E, et al. ALK-Positive Squamous Cell Carcinoma Dramatically Responded to Alectinib. Case Rep Oncol Med 2018;2018:4172721. [Crossref] [PubMed]
31. Tamiya A, Shimizu S, Atagi S. A Case of Squamous Cell Carcinoma Harboring an EML4-ALK Rearrangement that Was Unsuccessfully Treated with the ALK Inhibitor Alectinib. J Thorac Oncol 2015;10:e74. [Crossref] [PubMed]
32. Zhou C, Kim SW, Reungwetwattana T, et al. Alectinib versus crizotinib in untreated Asian patients with anaplastic lymphoma kinase-positive non-small-cell lung cancer (ALESIA): a randomised phase 3 study. Lancet Respir Med 2019;7:437-46. [Crossref] [PubMed]
33. Alidousty C, Becker A, Binot E, et al. Frequency and functional characterization of fusion genes in squamous cell carcinoma of the lung. Gene 2024;895:148018. [Crossref] [PubMed]
34. Zhang M, Huang Q, Yu M, et al. Immunotherapy for non-small cell lung cancer with EGFR or HER2 exon 20 insertion mutations: a real-world analysis. Transl Lung Cancer Res 2023;12:797-807. [Crossref] [PubMed]
35. Yang XR, Zhong SM, Jin ZY, et al. EGFR exon 20 insertion mutation and MET exon 14 skipping mutation in non-small cell lung cancer: a scoping review in the Chinese population. Transl Lung Cancer Res 2024;13:3224-40. [Crossref] [PubMed]
36. Guan Y, Feng D, Yin B, et al. Immune-related dissociated response as a specific atypical response pattern in solid tumors with immune checkpoint blockade. Ther Adv Med Oncol 2022;14:17588359221096877. [Crossref] [PubMed]
37. Sheikhbahaei S, Marcus CV, Sadaghiani MS, et al. Imaging of Cancer Immunotherapy: Response Assessment Methods, Atypical Response Patterns, and Immune-Related Adverse Events, From the AJR Special Series on Imaging of Inflammation. AJR Am J Roentgenol 2022;218:940-52. [Crossref] [PubMed]
38. Sato Y, Morimoto T, Hara S, et al. Dissociated response and clinical benefit in patients treated with nivolumab monotherapy. Invest New Drugs 2021;39:1170-8. [Crossref] [PubMed]
39. Tozuka T, Kitazono S, Sakamoto H, et al. Dissociated responses at initial computed tomography evaluation is a good prognostic factor in non-small cell lung cancer patients treated with anti-programmed cell death-1/ligand 1 inhibitors. BMC Cancer 2020;20:207. [Crossref] [PubMed]
40. Zhou H, Sun Y, Xiu W, et al. Overall survival benefit of continuing immune checkpoint inhibitors treatment post dissociated response in patients with advanced lung cancer. J Cancer Res Clin Oncol 2020;146:2979-88. [Crossref] [PubMed]
41. Zhou C, Hu Y, Arkania E, et al. A global phase 3 study of serplulimab plus chemotherapy as first-line treatment for advanced squamous non-small-cell lung cancer (ASTRUM-004). Cancer Cell 2024;42:198-208.e3. [Crossref] [PubMed]
42. Paz-Ares L, Vicente D, Tafreshi A, et al. A Randomized, Placebo-Controlled Trial of Pembrolizumab Plus Chemotherapy in Patients With Metastatic Squamous NSCLC: Protocol-Specified Final Analysis of KEYNOTE-407. J Thorac Oncol 2020;15:1657-69. [Crossref] [PubMed]
43. Sarode P, Mansouri S, Karger A, et al. Epithelial cell plasticity defines heterogeneity in lung cancer. Cell Signal 2020;65:109463. [Crossref] [PubMed]
44. Dentro SC, Leshchiner I, Haase K, et al. Characterizing genetic intra-tumor heterogeneity across 2,658 human cancer genomes. Cell 2021;184:2239-2254.e39. [Crossref] [PubMed]
45. Hino H, Utsumi T, Maru N, et al. Results of emergency salvage lung resection after chemo- and/or radiotherapy among patients with lung cancer. Interact Cardiovasc Thorac Surg 2022;35:ivac043. [Crossref] [PubMed]
46. Ohtaki Y, Shimizu K, Suzuki H, et al. Salvage surgery for non-small cell lung cancer after tyrosine kinase inhibitor treatment. Lung Cancer 2021;153:108-16. [Crossref] [PubMed]
47. Smith A, Wali A, Montes A, et al. Salvage pulmonary resection in stages IIIb-IV lung cancer after treatment with immune checkpoint inhibitors case series and literature review. J Surg Oncol 2022;125:290-8. [Crossref] [PubMed]
48. Nagata S, Hamaji M, Ozasa H, et al. Salvage Surgery After Immune Checkpoint Inhibitors for Advanced Non-Small Cell Lung Cancer: Potential Association Between Immune-Related Adverse Events and Longer Survival. Clin Lung Cancer 2022;23:e321-4. [Crossref] [PubMed]

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