Efficacy of immunotherapy in advanced ALK-rearranged non-small cell lung cancer patients with disease progression on ALK-TKIs

Introduction

Lung cancer is the leading cause of cancer-related death, and non-small cell lung cancer (NSCLC) comprises 85% of all lung cancer cases (1-3). Approximately 3–5% of patients with pulmonary adenocarcinoma have anaplastic lymphoma kinase (ALK) rearrangement, with a higher prevalence observed in younger and non-smoking patients (4,5). Following the introduction of ALK-tyrosine kinase inhibitors (TKIs), the patients survival outcomes have greatly improved (6). The 5-year follow-up outcomes of the CROWN study (7) showed that patients treated with the first-line lorlatinib had a longer progression-free survival (PFS) (>60 months) compared to those treated with crizotinib. However, disease progression inevitably developed.

In recent years, immune-checkpoint inhibitors (ICIs), such as the anti-programmed death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) monoclonal antibodies and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) inhibitors, have become important treatment methods for patients without oncogene alterations (8,9). The efficacy of immunotherapy in patients with ALK-rearrangement remains unclear, and more research needs to be conducted using ICIs (10-12). The IMMUNOTARGET trial showed that ALK-rearrangement patients treated with immunotherapy had a PFS of 2.5 months (13). Besides, tumorigenesis is frequently accompanied by alterations in PD-L1 expression, which is an established predictor of immunotherapy efficacy (14). Critically, whether PD-L1 expression predicts ICI benefit remains unaddressed. This retrospective study aimed to evaluate immunotherapy efficacy in ALK-TKI-resistant NSCLC stratified by PD-L1 status. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-505/rc).

Methods

Patients

We retrospectively collected the data of 556 patients with ALK-rearrangement treated at the Shanghai Chest Hospital between June 2018 and December 2022 from the hospital database. To be eligible for inclusion in the study, the patients had to meet the following inclusion criteria: (I) had been diagnosed with advanced NSCLC; (II) had ALK-rearrangement; (III) had received at least one type of ALK-TKI before treatment; and (IV) had received chemotherapy or immunotherapy after the development of ALK-TKI resistance. Patients were excluded from the study if they met any of the following exclusion criteria: (I) did not show disease progression after TKI treatment; (II) had other types of tumors; (III) had incomplete clinical information; (IV) were lost to follow-up; and/or (V) had received chemotherapy or immunotherapy as a first-line treatment. In total, 89 eligible patients were included in the study. The selection process is shown in Figure 1.

Figure 1 Flow chart of the selection process. ALK, anaplastic lymphoma kinase; NSCLC, non-small cell lung cancer; TKI, tyrosine kinase inhibitor.

The retrospective study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Review Board of the Shanghai Chest Hospital (No. IS24006). Informed consent was waived from patients due to the retrospective nature of this study. The recorded data occurred in April 2024. Telephone interviews were also used to verify the information and to contact patients who were not followed regularly. If a patient died, the date of death was taken as the last follow-up time.

Detection of genes and PD-L1 tumor cell proportion score (TPS)

PD-L1 status and molecular alterations status were measured in archival and/or freshly obtained tumor tissues. Gene detection was performed using either next-generation sequencing or the polymerase chain reaction (PCR)-based single-gene assay (LungCureCDx, Burning Rock, Suzhou, China). PD-L1 expression was detected by the PD-L1 immunohistochemical (IHC) 22C3 pharmDx assay (Agilent Technologies China, Beijing, China). PD-L1 expression in tumor cells was confirmed using the TPS, with results stratified as: TPS <1% (negative), TPS 1–49% (low expression), and TPS ≥50% (high expression).

End points and assessments

The primary endpoint was progression-free survival (PFS). Patients underwent continuous survival follow-up during treatment and quarterly post-discontinuation.

Secondary endpoints included overall survival (OS), disease control rate (DCR), PD-L1-based efficacy, and patient-reported outcomes.

Tumor staging followed the International Association for the Study of Lung Cancer (IASLC) 8th edition tumor-node-metastasis (TNM) criteria. Response assessment employed Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1) via high-resolution chest computed tomography (CT) and abdominal ultrasound at 6–8-week intervals, with biannual brain magnetic resonance imaging (MRI) for asymptomatic baseline-negative patients. Safety analysis documented adverse events per Common Terminology Criteria for Adverse Events (CTCAE) v4.0. All imaging underwent dual review by experienced physicians and independent radiologists.

Statistical analysis

All the statistical evaluations were conducted according to the predefined plan as stated before. Median PFS, median OS, and survival differences between the groups were estimated using the Kaplan-Meier (KM) method and compared using the log-rank test. DCR was defined as the proportion of patients with the best overall response, including a complete response (CR), partial response (PR), or stable disease (SD). Univariate and multivariate Cox regression was used to identify significant factors related to PFS. SPSS version 24.0 (IBM Corporation, Armonk, NY, USA) was used for all the statistical analysis. Differences were considered statistically significant when P<0.05.

Results

Patients characteristics

The final analysis included 89 patients between June 1, 2018, and December 31, 2022, who met the selection criteria. The study flow chart of the selection process is shown in Figure 1. Cohorts comprised 52 receiving immunotherapy (29 with post-resistance re-biopsy) and 37 receiving non-immunotherapy (21 with re-biopsy). The immunotherapy cohort comprised 10 patients receiving ICI monotherapy and 42 receiving combination therapy (chemotherapy or anti-angiogenics). The non-immunotherapy cohort received chemotherapy regimens such as pemetrexed/paclitaxel/docetaxel plus carboplatin/cisplatin, or anti-angiogenic.

Baseline characteristics were balanced between cohorts (P>0.05, Table 1). Median age was 53.5 years, 44.9% male, and 85.4% had adenocarcinoma. Most patients (93.3%) had Eastern Cooperative Oncology Group (ECOG)-Performance Status (PS) 0–1. Resistance developed after 1st- (16.9%), 2nd- (71.9%), or 3rd-generation (11.2%) ALK-TKIs. ALK-TKIs were discontinued before initiating further-line regimens to avoid potential synergistic toxicity. Treatment lines included 2nd-line (42.7%), 3rd-line (28.1%), or later (29.2%). No unexpected immune-related adverse events occurred.

PD-L1 expression

PD-L1 expression was assessed in all patients: 61 (68.5%) were positive (TPS ≥1%), including 39 (43.8%) with high expression (TPS ≥50%). The immunotherapy cohort comprised 37 PD-L1-positive patients, of whom 24, had a PD-L1 TPS ≥50%.

Before salvage therapy, 50 patients (56.2%) underwent re-biopsy for PD-L1 assessment. Of these patients, 16 (32.0%) had negative PD-L1 expression, 34 (68.0%) had positive PD-L1 expression, and 25 (50.0%) had a PD-L1 TPS ≥50%. In the immunotherapy cohort, 8 patients had negative PD-L1 expression, 21 had positive PD-L1 expression, and 18 (50.0%) had a PD-L1 TPS ≥50%.

Clinical outcomes

All enrolled patients

In the entire cohort, the median follow-up time was 33.4 months, the median PFS was 3.7 months, and the median OS from the start of the further-line treatment was 9.2 months. The patients who treated with immunotherapy had better PFS than those who treated without immunotherapy {median PFS [95% confidence interval (CI)]: 5.3 (3.2–7.5) vs. 2.5 (1.8–3.3) months; P=0.009} (Figure 2A). Among the PD-L1-positive patients, the median PFS of the immunotherapy patients was 7.1 months (95% CI: 5.8–8.5), while that of the patients without immunotherapy was 2.5 months (95% CI: 1.7–3.3), and the difference was statistically significant (P=0.02) (Figure 2B). In relation to the patients with a PD-L1 TPS ≥50%, those who received immunotherapy had a median PFS of 7.1 months, while those who received non-immunotherapy had a median PFS of 2.7 months (P=0.043) (Figure 2C). However, no such statistically significant difference was observed in the PD-L1-negative patients (median PFS for with immunotherapy vs. without immunotherapy: 1.5 vs. 2.9 months; P=0.68) (Figure 2D).

Figure 2 Graphs showing the PFS of all the enrolled patients (A); PD-L1 positive (TPS ≥1%) patients (B); PD-L1 high (TPS ≥50%) patients (C); PD-L1 negative (TPS <1%) patients (D). PFS, progression-free survival; PD-L1, programmed cell death ligand 1; TPS, tumor proportion score.

No significant OS benefit was observed with immunotherapy in the overall cohort [median OS: 14.6 vs. 18.4 months; hazard ratio (HR) =1.49, P=0.27] (Figure S1A) or PD-L1 subgroups (all P>0.05, Figure S1B-S1D). This may relate to subsequent therapies post-progression, which potentially confounded OS interpretation.

Univariate Cox analysis (significance threshold P<0.2) identified age (P=0.17), ECOG PS (P=0.047), and PD-L1 expression (P<0.001) as PFS correlates. Subsequent multivariate analysis confirmed that an age over 65 years, a better ECOG-PS, and positive PD-L1 expression were independent predictors of PFS (P=0.07, 0.02, and 0.001, respectively) (Table 2).

Patients who underwent re-biopsy after the development of TKI resistance

In relation to the patients who underwent re-biopsy after the development of ALK-TKI resistance, those who treated with immunotherapy had better PFS than those who treated without immunotherapy [median PFS (95% CI): 5.3 (2.2–8.5) vs. 2.5 (1.3–3.8) months; P=0.002] (Figure 3A). The differences were also significant among the PD-L1-positive patients [median PFS (95% CI): 7.8 (4.8–10.8) vs. 2.5 (1.0–4.1) months; P<0.001] (Figure 3B), and those who had a PD-L1 TPS ≥50% (median PFS: 7.8 vs. 2.7 months; P=0.002) (Figure 3C). In addition, the PD-L1-negative patients who received immunotherapy had a median PFS of 1.4 months, while those who received non-immunotherapy had a median PFS of 1.7 months (P=0.10) (Figure 3D).

Figure 3 Graphs showing the PFS of the patients who underwent re-biopsy after the development of TKI resistance: all the re-biopsy patients (A); re-biopsy patients with PD-L1 positive (TPS ≥1%) (B); re-biopsy patients with PD-L1 high (TPS ≥50%) (C); re-biopsy patients with PD-L1 negative (TPS <1%) (D). PFS, progression-free survival; TKI, tyrosine kinase inhibitor; PD-L1, programmed cell death ligand 1; TPS, tumor proportion score.

Among 50 patients undergoing post-resistance PD-L1 testing, 33 received their first-time PD-L1 evaluation and 17 had paired pre-/post-TKI samples. PD-L1 expression increased in 11 (64.7%) after resistance development (Figure S2A), while decreasing in the rest (35.3%).

Patients receiving immunotherapy

The immunotherapy cohort had a median PFS of 4.4 months. The PD-L1-positive patients had better PFS than the PD-L1-negative patients (median PFS: 7.1 vs. 1.5 months; P=0.004) (Figure 4A). The median PFS of the PD-L1 TPS <1%, 1–49%, and ≥50% was 1.5, 6.3, and 7.1 months, respectively (P=0.01) (Figure 4B).

Figure 4 Graphs showing the PFS of the patients in immunotherapy cohort according to PD-L1 expression: (A,B) the entire cohort; (C,D) underwent re-biopsy after the development of targeted resistance. PFS, progression-free survival; PD-L1, programmed cell death ligand 1; TPS, tumor proportion score.

In relation to the patients who underwent re-biopsy after the development of ALK-TKI resistance, the difference in terms of PFS was significant (median PFS: 7.8 vs. 1.4 months; P<0.001) (Figure 4C) between those with positive and negative PD-L1 expression. Differences in PFS were also observed among the PD-L1 TPS <1%, 1–49%, and ≥50% patients (median PFS: 1.4, 8.4, and 7.8 months; P <0.001) (Figure 4D).

Univariate analysis in the immunotherapy cohort confirmed significantly longer PFS for PD-L1-positive versus PD-L1-negative patients (HR 0.383, 95% CI: 0.195-0.751; P=0.005) (Figure 5). The DCR of the population of eligible patients was 89.29%, and 17 patients had SD while 8 patients had PR (Figure S2B).

Figure 5 Univariate Cox regression analysis of PFS in patients receiving immunotherapy. ALK, anaplastic lymphoma kinase; CI, confidence interval; HR, hazard ratio; PD-L1, programmed cell death ligand 1; PFS, progression-free survival; TNM, the 8th edition of tumor-node-metastasis classification; TKI, tyrosine kinase inhibitor.

Discussion

There are different treatment regimens for patients with advanced NSCLC (15,16). TKIs are recommended as the first-line treatment for patients with ALK-rearrangement (17,18). TKIs significantly prolong the survival of ALK-rearranged NSCLC patients; however, drug resistance always develops. This study aimed to assess the efficacy of immunotherapy in ALK-TKI-resistant NSCLC patients, stratified by PD-L1 expression. Our findings demonstrated that PD-L1 expression predicts clinical benefit from immunotherapy, with PD-L1-positive patients achieving significantly prolonged PFS compared to non-immunotherapy counterparts (median PFS 7.1 vs. 2.5 months; P=0.02). This contrasts with historical studies of limited immune checkpoint inhibitor efficacy in unselected ALK-positive cohorts. One study, that used the health record and treatment history data of 83 ALK-rearranged NSCLC patients who received immunotherapy, demonstrated a median time to disease progression of 2.34 months (19). Another real-world study showed that the median PFS was 2.4 months among pretreated ALK-rearranged patients (20). The possible mechanism for the poor efficacy of the immunotherapy treatment may be the lack of CD8⁺ T cells and the enriched population of resting memory CD4⁺ T cells (21). Another study showed that ALK-fusion patients had a lower expression of activated immune markers, such as CD8 and Granzyme B, and a higher expression of immunosuppressive markers, such as tumour immune microenvironments (TIMs), than Kirsten rat sarcoma homolog (KRAS)-mutated patients (22). These critical divergences underscored the necessity of biomarker-driven patient selection when considering salvage immunotherapy.

PD-L1 serves as a predictive biomarker for evaluating the sensitivity of ICIs in many tumor types. However, the association between PD-L1 expression and treatment efficacy among ALK-rearranged patients has not been examined. In our study, PD-L1-positive status (TPS ≥1%) was associated with improved outcomes from immunotherapy, whereas no significant benefit was observed in PD-L1-negative patients (1.5 vs. 2.9 months; P=0.68). This observation may provide a potential explanation for the variable efficacy reported in prior studies: Vokes et al. systematically reviewed clinical trials about ICIs treatment, revealing that ALK-driven NSCLC derived limited clinical benefit from PD-1/L1 inhibitors with median PFS less than 3 months (23); a case report described a lorlatinib-resistant patient who benefited from nivolumab, who achieved the best response of nearly complete remission, with a duration of over 21 months (24). Our findings may suggest that PD-L1 status may help reconcile these discrepancies.

Importantly, we observed that PD-L1 assessment after TKI resistance through re-biopsy may offer enhanced predictive utility. Among 50 re-biopsy patients, the immunotherapy-treated PD-L1-positive patients achieved a median PFS of 7.8 months versus 2.7 months for non-immunotherapy (P=0.002). These findings align with evidence of temporal PD-L1 dynamics: 64.7% of paired biopsies showed expression upregulation after TKI resistance. Previous studies have shown that the upregulation of PD-L1 could serve as a biomarker for ALK-rearranged NSCLC (25-27).

Such plasticity reflects TKI-induced remodeling of the tumor microenvironment (TME). Researches have shown that immune scores and microenvironment scores are significantly increased in post ALK-TKI treatment samples, which can enhance the antitumor response of immunotherapy (28,29). A systematic review further concluded that there were synergistic effects in combination regimens related to increasing the ratio of antitumor immune cells (30). The IMpower 150 subgroup analysis revealed that the median PFS of patients previously treated with EGFR- or ALK-TKIs who received immunotherapy plus anti-angiogenesis reached 6.8 months, which may contribute to this regimens combination (31). JAVELIN Renal 101 also demonstrated synergistic efficacy of avelumab plus axitinib versus sunitinib, with doubled objective response rate (ORR) (59.7% vs. 32.0%), prolonged PFS, and durable responses (16.4% ≥5-year responders), despite non-significant OS trend confounded by subsequent immunotherapy (32). However, our limited sample size precluded similar conclusions, warranting future studies on combination immunotherapy efficacy and beneficiary patient subgroups.

These findings advocate for necessary re-biopsy at ALK-TKI progression to guide therapeutic sequencing. Immunotherapy could be prioritized for patients with PD-L1-positive re-biopsies, particularly those with high expression (TPS ≥50%; PFS 7.8 months). This approach can also address the urgent unmet need in lorlatinib-resistant disease (representing 11.2% of our cohort).

This study had some limitations. First, it was a retrospective, single-center study, which inevitably caused selection bias. Second, the small sample size might have affected the reliability of the outcomes, especially those for the subgroup analysis. Finally, the absence of overall survival benefit likely reflects confounding from heterogeneous subsequent therapies, particularly the prevalent use of later-generation ALK-TKIs such as lorlatinib following progression, which may independently extend survival. Prospective studies remain necessary to validate these observations and refine biomarker-directed strategies.

Conclusions

This was the first study to show that some patients with positive PD-L1 expression can benefit from immune-based therapy after the development of ALK-TKI resistance. We recommend that patients undergo a biopsy to detect molecular alterations and PD-L1 status after the development of targeted resistance, as this reflects the proper immune environment and thus may explore the potential ALK-TKI resistance mechanisms and offer better guidance for further treatment.

Acknowledgments

The authors would like to thank all the participants and investigators for their involvement in this work.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-505/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-505/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-505/prf

Funding: This work was supported by the National Natural Science Foundation of China (No. 82273124) and Research Project of Shanghai Municipal Health Commission (No. 202140043).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-505/coif). E.M.U. has received research grants from AstraZeneca and Merck; speaker fees from Amgen, Janssen and MSD; travel support related to participation in international scientific meeting from AstraZeneca, MSD, and Roche; payment for participation in Advisory Board from AstraZeneca and Pfizer. D.K.G. received consulting fees from AstraZeneca, Takeda, Pfizer, Boehringer-Ingelheim, BMS, Janssen and MSD; payment or honoraria from Daiichi Sankyo and Roche; support for attending meetings and/or travel from Takeda, Pfizer, Janssen, Daiichi Sankyo and AstraZeneca. The other 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. The retrospective study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Review Board of the Shanghai Chest Hospital (No. IS24006). Individual consent for this retrospective analysis was waived.

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. Leiter A, Veluswamy RR, Wisnivesky JP. The global burden of lung cancer: current status and future trends. Nat Rev Clin Oncol 2023;20:624-39. [Crossref] [PubMed]
2. Siegel RL, Kratzer TB, Giaquinto AN, et al. Cancer statistics, 2025. CA Cancer J Clin 2025;75:10-45. [Crossref] [PubMed]
3. Miller KD, Nogueira L, Devasia T, et al. Cancer treatment and survivorship statistics, 2022. CA Cancer J Clin 2022;72:409-36. [Crossref] [PubMed]
4. Jordan EJ, Kim HR, Arcila ME, et al. Prospective Comprehensive Molecular Characterization of Lung Adenocarcinomas for Efficient Patient Matching to Approved and Emerging Therapies. Cancer Discov 2017;7:596-609. [Crossref] [PubMed]
5. Devarakonda S, Morgensztern D, Govindan R. Genomic alterations in lung adenocarcinoma. Lancet Oncol 2015;16:e342-51. [Crossref] [PubMed]
6. 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. [Crossref] [PubMed]
7. Solomon BJ, Liu G, Felip E, et al. Lorlatinib Versus Crizotinib in Patients With Advanced ALK-Positive Non-Small Cell Lung Cancer: 5-Year Outcomes From the Phase III CROWN Study. J Clin Oncol 2024;42:3400-9. [Crossref] [PubMed]
8. 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]
9. Negrao MV, Lam VK, Reuben A, et al. PD-L1 Expression, Tumor Mutational Burden, and Cancer Gene Mutations Are Stronger Predictors of Benefit from Immune Checkpoint Blockade than HLA Class I Genotype in Non-Small Cell Lung Cancer. J Thorac Oncol 2019;14:1021-31. [Crossref] [PubMed]
10. Dantoing E, Piton N, Salaün M, et al. Anti-PD1/PD-L1 Immunotherapy for Non-Small Cell Lung Cancer with Actionable Oncogenic Driver Mutations. Int J Mol Sci 2021;22:6288. [Crossref] [PubMed]
11. Tan AC, Chan J, Khasraw M. The role of immunotherapy in fusion-driven lung cancer. Expert Rev Anticancer Ther 2021;21:461-4. [Crossref] [PubMed]
12. Guaitoli G, Tiseo M, Di Maio M, et al. Immune checkpoint inhibitors in oncogene-addicted non-small cell lung cancer: a systematic review and meta-analysis. Transl Lung Cancer Res 2021;10:2890-916. [Crossref] [PubMed]
13. 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;30:1321-8. [Crossref] [PubMed]
14. Reck M, Rodríguez-Abreu D, Robinson AG, et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med 2016;375:1823-33. [Crossref] [PubMed]
15. Wang M, Herbst RS, Boshoff C. Toward personalized treatment approaches for non-small-cell lung cancer. Nat Med 2021;27:1345-56. [Crossref] [PubMed]
16. Chen R, Manochakian R, James L, et al. Emerging therapeutic agents for advanced non-small cell lung cancer. J Hematol Oncol 2020;13:58. [Crossref] [PubMed]
17. Ou SI, Solomon BJ, Shaw AT, et al. Continuation of Lorlatinib in ALK-Positive NSCLC Beyond Progressive Disease. J Thorac Oncol 2022;17:568-77. [Crossref] [PubMed]
18. Bearz A, De Carlo E, Del Conte A, et al. The Change in Paradigm for NSCLC Patients with EML4-ALK Translocation. Int J Mol Sci 2022;23:7322. [Crossref] [PubMed]
19. Jahanzeb M, Lin HM, Pan X, et al. Immunotherapy Treatment Patterns and Outcomes Among ALK-Positive Patients With Non-Small-Cell Lung Cancer. Clin Lung Cancer 2021;22:49-57. [Crossref] [PubMed]
20. Heo JY, Park C, Keam B, et al. The efficacy of immune checkpoint inhibitors in anaplastic lymphoma kinase-positive non-small cell lung cancer. Thorac Cancer 2019;10:2117-23. [Crossref] [PubMed]
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. [Crossref] [PubMed]
22. Tian X, Li Y, Huang Q, et al. High PD-L1 Expression Correlates with an Immunosuppressive Tumour Immune Microenvironment and Worse Prognosis in ALK-Rearranged Non-Small Cell Lung Cancer. Biomolecules 2023;13:991. [Crossref] [PubMed]
23. Vokes NI, Pan K, Le X. Efficacy of immunotherapy in oncogene-driven non-small-cell lung cancer. Ther Adv Med Oncol 2023;15:17588359231161409. [Crossref] [PubMed]
24. Shokhanda S, Jain P, Garg A, et al. Complete and Durable response to Immunotherapy in ALK-re-arranged Advanced Lung Adenocarcinoma NSCLC: a Case Report. Conference: Global immunology summit 2024. DOI: 10.3389/fonc.2022.101686.
25. Parvaresh H, Roozitalab G, Golandam F, et al. Unraveling the Potential of ALK-Targeted Therapies in Non-Small Cell Lung Cancer: Comprehensive Insights and Future Directions. Biomedicines 2024;12:297. [Crossref] [PubMed]
26. Sposito M, Eccher S, Pasqualin L, et al. Characterizing the immune tumor microenvironment in ALK fusion-positive lung cancer: state-of-the-art and therapeutical implications. Expert Rev Clin Immunol 2024;20:959-70. [Crossref] [PubMed]
27. Schenk EL. Narrative review: immunotherapy in anaplastic lymphoma kinase (ALK)+ lung cancer-current status and future directions. Transl Lung Cancer Res 2023;12:322-36. [Crossref] [PubMed]
28. Schneider JL, Lin JJ, Shaw AT. ALK-positive lung cancer: a moving target. Nat Cancer 2023;4:330-43. [Crossref] [PubMed]
29. Fang Y, Wang Y, Zeng D, et al. Comprehensive analyses reveal TKI-induced remodeling of the tumor immune microenvironment in EGFR/ALK-positive non-small-cell lung cancer. Oncoimmunology 2021;10:1951019. [Crossref] [PubMed]
30. Yi M, Jiao D, Qin S, et al. Synergistic effect of immune checkpoint blockade and anti-angiogenesis in cancer treatment. Mol Cancer 2019;18:60. [Crossref] [PubMed]
31. Nogami N, Barlesi F, Socinski MA, et al. IMpower150 Final Exploratory Analyses for Atezolizumab Plus Bevacizumab and Chemotherapy in Key NSCLC Patient Subgroups With EGFR Mutations or Metastases in the Liver or Brain. J Thorac Oncol 2022;17:309-23.
32. Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med 2019;380:1103-15. [Crossref] [PubMed]