Top

BMC Cancer

Published in:

Open Access 01-12-2024 | NSCLC | Research

Response to immune checkpoint inhibitor combination therapy in metastatic RET-mutated lung cancer from real-world retrospective data

Authors: Ningning Yan, Huixian Zhang, Shujing Shen, Sanxing Guo, Xingya Li

Published in: BMC Cancer | Issue 1/2024

Abstract

Background

The impact of immune checkpoint inhibitors (ICIs) based treatments on non-small cell lung cancers (NSCLCs) with RET fusions remains poorly understood.

Methods

We screened patients with RET fusions at the First Affiliated Hospital of Zhengzhou University and included those who were treated with ICIs based regimens for further analysis. We evaluated clinical indicators including objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS).

Results

A total of 232 patients with RET fusions were included in the study. Of these, 129 patients had their programmed death-ligand 1 (PDL1) expression levels tested, with 22 patients (17.8%) having a PDL1 level greater than or equal to 50%. Additionally, tumor mutational burden (TMB) status was evaluated in 35 patients, with the majority (30/35, 85.8%) having a TMB of less than 10 mutations per megabase. Out of the 38 patients treated with ICI based regimens, the median PFS was 5 months (95% confidence interval [CI]: 2.4–7.6 months) and the median OS was 19 months (95% CI: 9.7–28.3 months) at the time of data analysis. Stratification based on treatment lines did not show any significant differences in OS (18 vs. 19 months, p = 0.63) and PFS (6 vs. 5 months, p = 0.86). The ORR for patients treated with ICIs was 26.3%. Furthermore, no significant differences were found for PFS (p = 0.27) and OS (p = 0.75) between patients with positive and negative PDL1 expression. Additionally, there was no significant difference in PD-L1 levels (p = 0.10) between patients who achieved objective response and those who did not.

Conclusions

Patients with RET fusion positive NSCLCs may not benefit from ICI based regimens and therefore should not be treated with ICIs in clinical practice.

Available only for authorised users

Sholl LM, Aisner DL, Varella-Garcia M, Berry LD, Dias-Santagata D, Wistuba II, et al. Multi-institutional Oncogenic Driver Mutation Analysis in Lung Adenocarcinoma: the Lung Cancer Mutation Consortium Experience. J Thorac Oncol. 2015;10(5):768–77.CrossRefPubMedPubMedCentral

Steuer CE, Behera M, Berry L, Kim S, Rossi M, Sica G, et al. Role of race in oncogenic driver prevalence and outcomes in lung adenocarcinoma: results from the Lung Cancer Mutation Consortium. Cancer. 2016;122(5):766–72.CrossRefPubMed

Adashek JJ, Desai AP, Andreev-Drakhlin AY, Roszik J, Cote GJ, Subbiah V. Hallmarks of RET and co-occuring genomic alterations in RET-aberrant cancers. Mol Cancer Ther. 2021;20(10):1769–76.CrossRefPubMedPubMedCentral

Ferrara R, Auger N, Auclin E, Besse B. Clinical and translational implications of RET rearrangements in Non-small Cell Lung Cancer. J Thorac Oncol. 2018;13(1):27–45.CrossRefPubMed

Osta BE, Ramalingam SS. RET Fusion: joining the ranks of Targetable Molecular drivers in NSCLC. JTO Clin Res Rep. 2020;1(3):100050.PubMedPubMedCentral

Drilon A, Wang L, Hasanovic A, Suehara Y, Lipson D, Stephens P, et al. Response to Cabozantinib in patients with RET fusion-positive lung adenocarcinomas. Cancer Discov. 2013;3(6):630–5.CrossRefPubMedPubMedCentral

Cascetta P, Sforza V, Manzo A, Carillio G, Palumbo G, Esposito G et al. RET Inhibitors in Non-Small-Cell Lung Cancer. Cancers (Basel) 2021, 13(17).

Lee SH, Lee JK, Ahn MJ, Kim DW, Sun JM, Keam B, et al. Vandetanib in pretreated patients with advanced non-small cell lung cancer-harboring RET rearrangement: a phase II clinical trial. Ann Oncol. 2017;28(2):292–7.CrossRefPubMed

Gainor JF, Curigliano G, Kim DW, Lee DH, Besse B, Baik CS, et al. Pralsetinib for RET fusion-positive non-small-cell lung cancer (ARROW): a multi-cohort, open-label, phase 1/2 study. Lancet Oncol. 2021;22(7):959–69.CrossRefPubMed

10.

Drilon A, Oxnard GR, Tan DSW, Loong HHF, Johnson M, Gainor J, et al. Efficacy of Selpercatinib in RET Fusion-positive non-small-cell Lung Cancer. N Engl J Med. 2020;383(9):813–24.CrossRefPubMedPubMedCentral

11.

Zhou C, Solomon B, Loong HH, Park K, Pérol M, Arriola E, et al. First-line selpercatinib or chemotherapy and Pembrolizumab in RET Fusion-positive NSCLC. N Engl J Med. 2023;389(20):1839–50.CrossRefPubMed

12.

Mazieres J, Drilon A, Lusque A, Mhanna L, Cortot AB, Mezquita L, et al. Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET registry. Ann Oncol. 2019;30(8):1321–8.CrossRefPubMedPubMedCentral

13.

Lisberg A, Cummings A, Goldman JW, Bornazyan K, Reese N, Wang T, et al. A phase II study of Pembrolizumab in EGFR-Mutant, PD-L1+, tyrosine kinase inhibitor Naïve patients with Advanced NSCLC. J Thorac Oncol. 2018;13(8):1138–45.CrossRefPubMedPubMedCentral

14.

Seegobin K, Majeed U, Wiest N, Manochakian R, Lou Y, Zhao Y. Immunotherapy in Non-small Cell Lung Cancer with actionable mutations other Than EGFR. Front Oncol. 2021;11:750657.CrossRefPubMedPubMedCentral

15.

Dudnik E, Bshara E, Grubstein A, Fridel L, Shochat T, Roisman LC, 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.CrossRefPubMed

16.

Guisier F, Dubos-Arvis C, Viñas F, Doubre H, Ricordel C, Ropert S, 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(4):628–36.CrossRefPubMed

17.

Baglivo S, Ludovini V, Moretti R, Bellezza G, Sidoni A, Roila F, et al. RET rearrangement as a predictor of unresponsiveness to Immunotherapy in Non-small Cell Lung Cancer: report of two cases with review of the literature. Oncol Ther. 2020;8(2):333–9.CrossRefPubMedPubMedCentral

18.

Hegde A, Andreev-Drakhlin AY, Roszik J, Huang L, Liu S, Hess K, et al. Responsiveness to immune checkpoint inhibitors versus other systemic therapies in RET-aberrant malignancies. ESMO Open. 2020;5(5):e000799.CrossRefPubMedPubMedCentral

19.

Offin M, Guo R, Wu SL, Sabari J, Land JD, Ni A et al. Immunophenotype and response to Immunotherapy of RET-Rearranged lung cancers. JCO Precis Oncol 2019, 3.

20.

Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive non-small-cell Lung Cancer. N Engl J Med. 2016;375(19):1823–33.CrossRefPubMed

21.

Marabelle A, Fakih M, Lopez J, Shah M, Shapira-Frommer R, Nakagawa K, et al. Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study. Lancet Oncol. 2020;21(10):1353–65.CrossRefPubMed

22.

Aldea M, Marinello A, Duruisseaux M, Zrafi W, Conci N, Massa G, et al. RET-MAP: an International Multicenter Study on Clinicobiologic Features and treatment response in patients with Lung Cancer harboring a RET Fusion. J Thorac Oncol. 2023;18(5):576–86.CrossRefPubMed

23.

Ju YS, Lee WC, Shin JY, Lee S, Bleazard T, Won JK, et al. A transforming KIF5B and RET gene fusion in lung adenocarcinoma revealed from whole-genome and transcriptome sequencing. Genome Res. 2012;22(3):436–45.

24.

Lee J, Ku BM, Shim JH, La Choi Y, Sun JM, Lee SH, 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(5):594–601.CrossRefPubMed

25.

Wang R, Hu H, Pan Y, Li Y, Ye T, Li C, et al. RET fusions define a unique molecular and clinicopathologic subtype of non-small-cell lung cancer. J Clin Oncol. 2012;30(35):4352–9.CrossRefPubMed

26.

Drilon A, Lin JJ, Filleron T, Ni A, Milia J, Bergagnini I, et al. Frequency of brain metastases and multikinase inhibitor outcomes in patients with RET-Rearranged lung cancers. J Thorac Oncol. 2018;13(10):1595–601.CrossRefPubMedPubMedCentral

27.

Negrao MV, Skoulidis F, Montesion M, Schulze K, Bara I, Shen V 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(8).

28.

Lu C, Dong XR, Zhao J, Zhang XC, Chen HJ, Zhou Q, et al. Association of genetic and immuno-characteristics with clinical outcomes in patients with RET-rearranged non-small cell lung cancer: a retrospective multicenter study. J Hematol Oncol. 2020;13(1):37.CrossRefPubMedPubMedCentral

29.

Jiang B, Hu L, Dong D, Guo Z, Wei W, Wang C, et al. TP53 or CDKN2A/B covariation in ALK/RET/ROS1-rearranged NSCLC is associated with a high TMB, tumor immunosuppressive microenvironment and poor prognosis. J Cancer Res Clin Oncol. 2023;149(12):10041–52.CrossRefPubMed

30.

Nagahashi M, Sato S, Yuza K, Shimada Y, Ichikawa H, Watanabe S, et al. Common driver mutations and smoking history affect tumor mutation burden in lung adenocarcinoma. J Surg Res. 2018;230:181–5.CrossRefPubMedPubMedCentral

31.

Wang X, Ricciuti B, Nguyen T, Li X, Rabin MS, Awad MM, et al. Association between Smoking History and Tumor Mutation Burden in Advanced Non-small Cell Lung Cancer. Cancer Res. 2021;81(9):2566–73.CrossRefPubMedPubMedCentral

32.

Madeddu C, Donisi C, Liscia N, Lai E, Scartozzi M, Macciò A. EGFR-Mutated Non-small Cell Lung Cancer and Resistance to Immunotherapy: role of the Tumor Microenvironment. Int J Mol Sci 2022, 23(12).

33.

Bhandari NR, Hess LM, Han Y, Zhu YE, Sireci AN. Efficacy of immune checkpoint inhibitor therapy in patients with RET fusion-positive non-small-cell lung cancer. Immunotherapy. 2021;13(11):893–904.CrossRefPubMed

34.

Akers KG, Oskar S, Zhao B, Frederickson AM, Arunachalam A. Clinical outcomes of PD-1/PD-L1 inhibitors among patients with Advanced or Metastatic Non-small Cell Lung Cancer with BRAF, ERBB2/HER2, MET, or RET alterations: a systematic literature review. J Immunother 2023.

35.

Long JY, Li RZ, Wang DX, Liu H, Tian J, Ding ZN, et al. Comprehensive molecular analysis identifies RET alterations association with response of ICIs in multi-immunotherapy cohorts. Int Immunopharmacol. 2023;126:111281.CrossRefPubMed

36.

Drilon A, Bergagnini I, Delasos L, Sabari J, Woo KM, Plodkowski A, et al. Clinical outcomes with pemetrexed-based systemic therapies in RET-rearranged lung cancers. Ann Oncol. 2016;27(7):1286–91.CrossRefPubMedPubMedCentral

Title: Response to immune checkpoint inhibitor combination therapy in metastatic RET-mutated lung cancer from real-world retrospective data
Authors: Ningning Yan
Huixian Zhang
Shujing Shen
Sanxing Guo
Xingya Li
Publication date: 01-12-2024
Publisher: BioMed Central
Keywords: NSCLC
NSCLC
Checkpoint Inhibitors
Lung Cancer
Lung Cancer
Lung Cancer
Published in: BMC Cancer / Issue 1/2024
Electronic ISSN: 1471-2407
DOI: https://doi.org/10.1186/s12885-024-11852-3

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2024

A preliminary study on the reference intervals of serum tumor marker in apparently healthy elderly population in southwestern China using real-world data

Germline mutations in BRCA1 and BRCA2 among Brazilian women with ovarian cancer treated in the Public Health System

Alpha-fetoprotein predicts the treatment efficacy of immune checkpoint inhibitors for gastric cancer patients

Correction: The value of oral selective estrogen receptor degraders in patients with HR-positive, HER2-negative advanced breast cancer after progression on ≥ 1 line of endocrine therapy: systematic review and meta-analysis

Impact of the Sars-Cov-2 outbreak on the initial clinical presentation of new solid cancer diagnoses: a systematic review and meta-analysis

Diabetes and the social, biologic, and behavioral determinants of endometrial cancer in the United States

Keynote webinar | Spotlight on antibody–drug conjugates in cancer