Immune checkpoint inhibitors for patients with gene-rearranged non-small cell lung cancer

Immune checkpoint inhibitors for patients with gene-rearranged non-small cell lung cancer

Yuji Uehara1,2^, Taiki Hakozaki1,3^

1Department of Thoracic Oncology and Respiratory Medicine, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan; 2Department of Precision Cancer Medicine, Center for Innovative Cancer Treatment, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan; 3Graduate School of Advanced Science and Engineering, Faculty of Science and Engineering, Waseda University, Tokyo, Japan

^ORCID: Yuji Uehara, 0000-0001-8047-8730; Taiki Hakozaki, 0000-0002-9980-4417.

Correspondence to: Taiki Hakozaki, MD. Department of Thoracic Oncology and Respiratory Medicine, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, 3-18-22 Honkomagome, Bunkyo, Tokyo, Japan. Email:

Comment on: Mushtaq R, Cortot AB, Gautschi O, et al. PD-1/PD-L1 inhibitor activity in patients with gene-rearrangement positive non-small cell lung cancer—an IMMUNOTARGET case series. Transl Lung Cancer Res 2022;11:2412-7.

Keywords: Immune checkpoint inhibitor (ICI); non-small cell lung cancer (NSCLC); gene rearrangement; biomarker; prognosis

Submitted Dec 07, 2022. Accepted for publication Dec 25, 2022. Published online Dec 26 2022.

doi: 10.21037/tlcr-22-872


Although first-line targeted therapies are the current standard-of-care treatment for non-small cell lung cancer (NSCLC) with driver alterations, therapeutic resistance is inevitable. Immune checkpoint inhibitor (ICI) regimens are one of the standard-of-care options after disease progression on targeted therapies. ICI improved the outcomes of metastatic NSCLC without driver alterations. Although the clinical benefit of ICI for patients with epidermal growth factor receptor (EGFR) alteration is limited, their efficacy in patients with other driver alterations is unknown because each driver alteration occurs in 1% to 5% of patients with NSCLC (1-3).

The IMMUNOTARGET registry was the first global multicenter registry to report the clinical outcomes of patients with NSCLC with EGFR, KRAS, ALK, BRAF, ROS1, HER2, RET, and MET alterations (2). The overall response rate in gene rearrangement was low in this registry [ALK, 0% (n=23); RET, 6% (n=16); ROS1, 17% (n=7)]. Similarly, prior studies have reported a limited response to ICI for gene-rearranged NSCLC regardless of programmed death-ligand 1 (PD-L1) status, but all of them have limitations due to small sample sizes and retrospective analyses (3-7). On the other hand, some patients with gene-rearranged NSCLC responded to ICI for a long time (8). Thus, in the case of gene-rearranged NSCLC, detailed information on who will benefit from ICI remains a major unmet need.

Mushtaq et al. (9) described the details of five cases with gene-rearranged NSCLC who had durable responses to ICI monotherapy in the IMMUNOTARGET registry (RET, n=1; ROS1, n=1) and an additional survey (ALK, n=2; RET, n=1; ROS1, n=1). Clinicopathologic features were used to determine whether these cases had true gene rearrangement. All cases had adenocarcinoma histology and no or little smoking history, which is consistent with true gene-rearranged NSCLC. Next-generation sequencing (NGS, CD74-ROS1) and nanostring technology (KIF5B-RET) were used to identify fusion partners in two cases. The ROS1 and RET cases received the robust clinical benefit of ICI and had immunotherapy PFS of 36 and 8 months, respectively. Only immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH) was used to diagnose two ALK cases. In patients with ALK rearrangement, 0.2–21% had discordant IHC and FISH results, and a single assay could result in false positive cases (10). While one of the two ALK cases had long-term benefits from crizotinib, indicating a true ALK rearrangement, another case had only <5 months of PFS, suggesting a false positive. The former ALK case had a 6.3-month immunotherapy PFS after receiving the clinical benefit of ICI. One RET case was recently described as “RET positive” with no prior exposure to RET inhibitors, raising questions about the existence of true RET rearrangement. The authors not only show that ICI is ineffective in gene-rearranged NSCLC but also cast doubt on the registry study’s diagnostic methods.

When we investigate cases of gene rearrangement that benefit from ICI, it is critical to validate whether they are true gene rearrangements, not least because the subset is small. The diagnostic methods used for molecular testing in previous studies varied (Table 1). Moreover, some studies have not reported details of molecular testing (11,12). As mentioned in ALK IHC, variations in diagnostic methods may result in the inclusion of false positive cases. For example, RET FISH had high sensitivity and low specificity, resulting in a high proportion of false positive results (18). Thus, the study using RET FISH may have included false positive cases, resulting in a higher ORR of 38% with ICI monotherapy, as opposed to the poor ORR of other studies (0–7.7%, Table 1) (6). Similarly, ROS1 FISH can result in a false positive, so confirmation by another method, such as NGS, is recommended (19). Multiplex DNR and/or RNA NGS techniques are recommended in the first-line setting due to their high sensitivity and specificity; however, they are not reimbursed in some countries or situations. In these cases, at the very least, confirmation is required, such as IHC screening followed by FISH confirmation (10).

Table 1

Efficacy of ICIs and diagnostic methods in patients with ALK/RET/ROS1-rearranged positive NSCLC

Reference Gene rearrangement Treatment ORR Median PFS (months) Diagnostic methods used for molecular testing Details of ICI-benefiting cases
Multicenter analysis by Mazieres et al. (2) ALK (n=23), RET (n=16), ROS1 (n=7) ICI monotherapy 0% (ALK), 6% (RET), 17% (ROS1) 2.5 (ALK), 2.1 (RET), NA (ROS1) Local testing on validated platforms NAa
Multicenter analysis by Negrao et al. (4) ALK (n=19), RET (n=14), ROS1 (n=3) ICI monotherapy NA 2.7 (overall) CLIA certified laboratory assays (most of them were FoundationOne assays) NA
Single-center analysis by Dudnik et al. (7) RET (n=4), ROS1 (n=1) ICI monotherapy 0% (RET), NA (ROS1) 3 (RET), 0.1 (ROS1) FoundationOne assay NA
Flatiron health electronic health record analysis by Jahanzeb et al. (11) ALK (n=83) ICI monotherapy (n=74) or ICI chemo (n=9) NA 2.3 Not specified NA
Flatiron health electronic health record analysis by Bodor et al. (12) ALK (n=65) ICI monotherapy (n=65) NA 2.3 Not specified NA
Single-center analysis by Oya et al. (13) ALK (n=7) ICI monotherapy NA 1.8 RT-PCR, IHC, or FISH NA
Single-center analysis by Gainor et al. (14) ALK (n=6) ICI monotherapy 0% NA FISH Not applicable
Multicenter analysis by Guisier et al. (6) RET (n=9) ICI monotherapy 38% 7.6 FISH NA
Single-center analysis by Offin et al. (15) RET (n=16) ICI monotherapy (n=15), dual ICIs (n=1) 0% 3.4 MSK-IMPACT, FoundationOne, multiplex PCR, FISH, or RT-PCR NA
Single-center analysis by Lee et al. (16) RET (n=13) ICI monotherapy (n=12), dual ICIs (n=1) 7.7% 2.1 FISH or NGS Available
Single-center analysis by Uehara et al. (5) RET (n=2) ICI chemo (n=2) 50% NA NGS (Oncomine Dx Target Test) NA
Multicenter analysis by Choudhury et al. (17) ROS1 (n=39) ICI monotherapy (n=28), ICI chemo (n=11) 13% (ICI monotherapy), 83% (ICI chemo) 2.1 (ICI monotherapy), 10 (ICI chemo) FISH or NGS. The details of NGS panels were described in the paper Available

a, it is available in the article that accompanies this editorial (9). ICI, immune checkpoint inhibitors; NSCLC, non-small cell lung cancer; ORR, overall response rate; PFS, progression-free survival; NA, not available; CLIA, clinical laboratory improvement amendment; chemo, chemotherapy; RT-PCR, reverse transcription polymerase chain reaction; IHC, immunohistochemistry; FISH, fluorescence in situ hybridization; NGS, next-generation sequencing.

A multicenter study is required to investigate the infrequent clinical outcomes of a small subset, such as gene-rearranged NSCLC that benefits from ICI. However, several important pieces of information were not reported in previous studies (Table 1). It is recommended to report diagnostic methods, fusion partners, and ICI-benefiting details for each case: sex, age, smoking, histology, and benefit from prior targeted therapy. Additionally, co-occurring genomic alterations would need to be documented because some co-alterations, such as STK11/KEAP1 or SMARCA4 alterations, can influence ICI efficacy (20,21). Although many items on case report forms influence the speed, with which data are collected for studies, the critical information associated with the validation of driver alterations should be collected. A global RET registry with a multicenter network is currently being established to collect clinical outcomes on ICI and their associations with clinicopathologic features (22). More registry work is needed in other cases of gene-rearranged NSCLC.

A post hoc analysis of prospective clinical trials may be able to address the issue of inconsistency in molecular testing caused by retrospective studies. ICI monotherapy has moved out of the standard of care in patients with driver alterations; it is difficult to use ICI monotherapy as a comparator arm. In a clinical trial of gene-rearranged NSCLC, ICI chemotherapy (ICI chemo) can be used as the comparator arm, allowing us to estimate ICI efficacy. Several phase III trials for first-line treatment of gene-rearranged NSCLC are currently underway to compare the efficacy of targeted therapy versus ICI chemo. LIBRETTO-431 (NCT04194944) is a randomized phase III trial comparing selpercatinib with carboplatin or cisplatin and pemetrexed chemotherapy with or without pembrolizumab in patients with metastatic RET-rearranged NSCLC who have not previously received treatment (23). Another phase III trial, AcceleRET Lung (NCT04222972), compares pralsetinib with chemotherapy with or without pembrolizumab as first-line treatment for metastatic RET-rearranged NSCLC (24). Further post hoc analysis of patients in the control arm who received ICI chemo is warranted to investigate, which clinicopathologic features affect the response to ICI, despite the fact that chemotherapy confounds their results. The Impower150 study [bevacizumab plus carboplatin plus paclitaxel (BCP) versus atezolizumab plus BCP] included 34 patients with ALK-rearranged NSCLC; however, no information on patients who responded to ABCP regimens was provided (25). On the other hand, similar phase III trials have not been conducted in patients with ROS1-rearranged NSCLC, and the clinical benefits of ICI regimens in patients with other driver alterations, such as MET, BRAF, HER2, NTRK, and NRG1, remain unknown. To understand the intertumor and intratumor heterogeneity of the immune response in these rare populations, international collaboration is required.


Funding: None.


Provenance and Peer Review: This article was commissioned by the editorial office, Translational Lung Cancer Research. The article did not undergo external peer review.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at TH received payment for speaker’s bureaus from Chugai Pharmaceutical, Ono Pharmaceutical, and Eisai, outside the submitted work. YU has 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.

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:


  1. Lee CK, Man J, Lord S, et al. Checkpoint Inhibitors in Metastatic EGFR-Mutated Non-Small Cell Lung Cancer-A Meta-Analysis. J Thorac Oncol 2017;12:403-7. [Crossref] [PubMed]
  2. 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]
  3. 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]
  4. 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]
  5. Uehara Y, Watanabe K, Hakozaki T, et al. Efficacy of first-line immune checkpoint inhibitors in patients with advanced NSCLC with KRAS, MET, FGFR, RET, BRAF, and HER2 alterations. Thorac Cancer 2022;13:1703-11. [Crossref] [PubMed]
  6. Guisier F, Dubos-Arvis C, Viñas F, et al. Efficacy and Safety of Anti-PD-1 Immunotherapy in Patients With Advanced NSCLC With BRAF, HER2, or MET Mutations or RET Translocation: GFPC 01-2018. J Thorac Oncol 2020;15:628-36. [Crossref] [PubMed]
  7. Dudnik E, Bshara E, Grubstein A, et al. Rare targetable drivers (RTDs) in non-small cell lung cancer (NSCLC): Outcomes with immune check-point inhibitors (ICPi). Lung Cancer 2018;124:117-24. [Crossref] [PubMed]
  8. Baldacci S, Grégoire V, Patrucco E, et al. Complete and prolonged response to anti-PD1 therapy in an ALK rearranged lung adenocarcinoma. Lung Cancer 2020;146:366-9. [Crossref] [PubMed]
  9. Mushtaq R, Cortot AB, Gautschi O, et al. PD-1/PD-L1 inhibitor activity in patients with gene-rearrangement positive non-small cell lung cancer—an IMMUNOTARGET case series. Transl Lung Cancer Res 2022;11:2412-7. [Crossref] [PubMed]
  10. Yatabe Y. ALK FISH and IHC: you cannot have one without the other. J Thorac Oncol 2015;10:548-50. [Crossref] [PubMed]
  11. 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]
  12. Bodor JN, Bauman JR, Handorf EA, et al. Real-world progression-free survival (rwPFS) and the impact of PD-L1 and smoking in driver-mutated non-small cell lung cancer (NSCLC) treated with immunotherapy. J Cancer Res Clin Oncol 2022; Epub ahead of print. [Crossref] [PubMed]
  13. Oya Y, Kuroda H, Nakada T, et al. Efficacy of Immune Checkpoint Inhibitor Monotherapy for Advanced Non-Small-Cell Lung Cancer with ALK Rearrangement. Int J Mol Sci 2020;21:2623. [Crossref] [PubMed]
  14. Gainor JF, Shaw AT, Sequist LV, et al. EGFR Mutations and ALK Rearrangements Are Associated with Low Response Rates to PD-1 Pathway Blockade in Non-Small Cell Lung Cancer: A Retrospective Analysis. Clin Cancer Res 2016;22:4585-93. [Crossref] [PubMed]
  15. Offin M, Guo R, Wu SL, et al. Immunophenotype and Response to Immunotherapy of RET-Rearranged Lung Cancers. JCO Precis Oncol 2019;3:PO.18.00386.
  16. Lee J, Ku BM, Shim JH, et al. Characteristics and outcomes of RET-rearranged Korean non-small cell lung cancer patients in real-world practice. Jpn J Clin Oncol 2020;50:594-601. [Crossref] [PubMed]
  17. Choudhury NJ, Schneider JL, Patil T, et al. Response to Immune Checkpoint Inhibition as Monotherapy or in Combination With Chemotherapy in Metastatic ROS1-Rearranged Lung Cancers. JTO Clin Res Rep 2021;2:100187. [PubMed]
  18. Radonic T, Geurts-Giele WRR, Samsom KG, et al. RET Fluorescence In Situ Hybridization Analysis Is a Sensitive but Highly Unspecific Screening Method for RET Fusions in Lung Cancer. J Thorac Oncol 2021;16:798-806. [Crossref] [PubMed]
  19. Heydt C, Ruesseler V, Pappesch R, et al. Comparison of in Situ and Extraction-Based Methods for the Detection of ROS1 Rearrangements in Solid Tumors. J Mol Diagn 2019;21:971-84. [Crossref] [PubMed]
  20. Zhou H, Shen J, Liu J, et al. Efficacy of Immune Checkpoint Inhibitors in SMARCA4-Mutant NSCLC. J Thorac Oncol 2020;15:e133-6. [Crossref] [PubMed]
  21. Rizvi H, Sanchez-Vega F, La K, et al. Molecular Determinants of Response to Anti-Programmed Cell Death (PD)-1 and Anti-Programmed Death-Ligand 1 (PD-L1) Blockade in Patients With Non-Small-Cell Lung Cancer Profiled With Targeted Next-Generation Sequencing. J Clin Oncol 2018;36:633-41. [Crossref] [PubMed]
  22. Drilon A, Lin JJ, Filleron T, et al. Frequency of Brain Metastases and Multikinase Inhibitor Outcomes in Patients With RET-Rearranged Lung Cancers. J Thorac Oncol 2018;13:1595-601. [Crossref] [PubMed]
  23. Solomon BJ, Zhou CC, Drilon A, et al. Phase III study of selpercatinib versus chemotherapy ± pembrolizumab in untreated RET positive non-small-cell lung cancer. Future Oncol 2021;17:763-73. [Crossref] [PubMed]
  24. Besse B, Felip E, Kim ES, et al. PUL01.02 AcceleRET Lung: A Phase 3 Study of First-Line Pralsetinib in Patients with RET-Fusion+ Advanced/Metastatic NSCLC. J Thorac Oncol 2021;16:S44-5. [Crossref]
  25. 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. [Crossref] [PubMed]
Cite this article as: Uehara Y, Hakozaki T. Immune checkpoint inhibitors for patients with gene-rearranged non-small cell lung cancer. Transl Lung Cancer Res 2023;12(1):6-10. doi: 10.21037/tlcr-22-872

Download Citation