Advertisement

The impact of TP53 co-mutations and immunologic microenvironment on outcome of lung cancer with EGFR exon 20 insertions

      Highlights

      • Platinum doublets and chemoimmunotherapy showed similar efficacy with ORR 20–25%.
      • TP53 mutations and brain metastases conferred shorter survival after platinum and TKI.
      • More tumour CD8+ and less Th1 cells were associated with longer overall survival.
      • No difference in outcome by exon20 insertion site or use of pemetrexed or bevacizumab.
      • Occasionally long responses under EGFR TKI for both ‘near-’ and ‘far-loop’ variants.

      Abstract

      Background

      EGFR exon20 insertions (ex20ins) are targeted by novel compounds in non-small-cell lung cancer (NSCLC). However, data about outcome under conventional therapies and the influence of molecular features are scarce.

      Patients and methods

      We retrospectively analysed 118 patients with evaluation of radiologic response based on RECIST v1.1. TP53 status was available for 88 cases.

      Results

      Platinum doublets and chemoimmunotherapy showed similar response rates (20–25%), disease control rates (80%) and median progression-free survival (mPFS, ≈7 months), which were longer compared to monochemotherapy (9%, 59%, 4.1 months), EGFR inhibitors (0%, 46%, 3.0) and PD-(L)1 inhibitors (0%, 30%, 2.1; p < 0.05). Overall survival (OS) was not dependent on the choice of first-line treatment, but related to more lines of systemic therapy (p < 0.05). TP53 mutations and brain metastases were associated with shorter PFS under platinum doublets and EGFR inhibitors (HR 3.3–6.1, p < 0.01), and shorter OS for patients receiving both treatments (p < 0.05). More tumour CD8+ and less Th1 cells were associated with longer OS independent of brain and TP53 status (p < 0.01). No difference in outcome was noted according to the ex20ins site and use of pemetrexed (vs. other cytotoxics) or bevacizumab. Long-lasting responses (>1 year) occasionally occurred under EGFR inhibitors for both ‘near-’ and ‘far-loop’ variants.

      Conclusions

      Platinum doublets and chemoimmunotherapy have the highest activity with ORR of 20–25% and mPFS of approximately 7 months, regardless of the cytotoxic partner, while PD-(L)1 inhibitors show limited efficacy. TP53 mutations, brain metastases and a lower tumour CD8/Th1-cell ratio are independently associated with shorter survival.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to European Journal of Cancer
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Burnett H.
        • Emich H.
        • Carroll C.
        • et al.
        Epidemiological and clinical burden of EGFR Exon 20 insertion in advanced non-small cell lung cancer: a systematic literature review.
        PLoS One. 2021; 16e0247620
        • Zhou C.
        • Ramalingam S.S.
        • Kim T.M.
        • 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; e214761
        • Park K.
        • Haura E.B.
        • Leighl N.B.
        • 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: 3391-3402
        • Friedlaender A.
        • Subbiah V.
        • Russo A.
        • et al.
        EGFR and HER2 exon 20 insertions in solid tumours: from biology to treatment.
        Nat Rev Clin Oncol. 2021; 19: 51-69
        • Hanna N.H.
        • Robinson A.G.
        • Temin S.
        • et al.
        Therapy for stage IV non-small-cell lung cancer with driver alterations: ASCO and OH (CCO) joint guideline update.
        J Clin Oncol. 2021; 39: 1040-1091
        • Robichaux J.P.
        • Le X.
        • Vijayan R.S.K.
        • et al.
        Structure-based classification predicts drug response in EGFR-mutant NSCLC.
        Nature. 2021; 597: 732-737
        • Riess J.W.
        • Gandara D.R.
        • Frampton G.M.
        • et al.
        Diverse EGFR exon 20 insertions and Co-occurring molecular alterations identified by comprehensive genomic profiling of NSCLC.
        J Thorac Oncol. 2018; 13: 1560-1568
        • Kirchner M.
        • Kluck K.
        • Brandt R.
        • et al.
        The immune microenvironment in EGFR- and ERBB2-mutated lung adenocarcinoma.
        ESMO Open. 2021; 6: 100253
        • Matsumoto Y.
        • Sawa K.
        • Fukui M.
        • et al.
        Impact of tumor microenvironment on the efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors in patients with EGFR-mutant non-small cell lung cancer.
        Cancer Sci. 2019; 110: 3244-3254
        • Christopoulos P.
        • Kirchner M.
        • Roeper J.
        • et al.
        Risk stratification of EGFR+ lung cancer diagnosed with panel-based next-generation sequencing.
        Lung Cancer. 2020; 148: 105-112
        • Volckmar A.-L.
        • Leichsenring J.
        • Kirchner M.
        • et al.
        Combined targeted DNA and RNA sequencing of advanced NSCLC in routine molecular diagnostics: analysis of the first 3,000 Heidelberg cases.
        Int J Cancer. 2019; 145: 649-661
        • König K.
        • Peifer M.
        • Fassunke J.
        • et al.
        Implementation of amplicon parallel sequencing leads to improvement of diagnosis and therapy of lung cancer patients.
        J Thorac Oncol. 2015; 10: 1049-1057
        • Elsayed M.
        • Bozorgmehr F.
        • Kazdal D.
        • et al.
        Feasibility and challenges for sequential treatments in ALK-rearranged non-small-cell lung cancer.
        Front Oncol. 2021; 11: 670483
        • Christopoulos P.
        • Grohé C.
        • Griesinger F.
        • et al.
        Real-world study of NSCLC with EGFR exon 20 insertions (ELCC 2021 Abstract 153P).
        J Thorac Oncol. 2021; 16: S780-S781
        • Christopoulos P.
        • Ou S.-H.
        • Lin J.
        • et al.
        Systematic review and meta-analysis of immunotherapy effectiveness for pretreated patients with non-small cell lung cancer harboring EGFR exon 20 insertions (ESMO 2021 congress abstract 1224P).
        Ann Oncol. 2021; 32: S972
        • Budczies J.
        • Kirchner M.
        • Kluck K.
        • et al.
        Deciphering the immunosuppressive tumor microenvironment in ALK- and EGFR-positive lung adenocarcinoma.
        Cancer Immunol Immunother. 2021;
        • Budczies J.
        • Kirchner M.
        • Kluck K.
        • et al.
        A gene expression signature associated with B cells predicts benefit from immune checkpoint blockade in lung adenocarcinoma.
        OncoImmunology. 2021; 10: 1860586
        • Danaher P.
        • Warren S.
        • Dennis L.
        • et al.
        Gene expression markers of tumor infiltrating leukocytes.
        J Immunother Cancer. 2017; 5: 18
        • Vasconcelos P.E.N.S.
        • Gergis C.
        • Viray H.
        • et al.
        EGFR-A763_Y764insFQEA is a unique exon 20 insertion mutation that displays sensitivity to approved and in-development lung cancer EGFR tyrosine kinase inhibitors.
        JTO Clin Res Rep. 2020; 1: 100051
        • Wu J.-Y.
        • Yu C.-J.
        • Shih J.-Y.
        Effectiveness of treatments for advanced non-small-cell lung cancer with exon 20 insertion epidermal growth factor receptor mutations.
        Clin Lung Cancer. 2019; 20: e620-e630
        • Yang G.
        • Li J.
        • Xu H.
        • et al.
        EGFR exon 20 insertion mutations in Chinese advanced non-small cell lung cancer patients: molecular heterogeneity and treatment outcome from nationwide real-world study.
        Lung Cancer. 2020; 145: 186-194
        • Leal J.L.
        • Alexander M.
        • Itchins M.
        • et al.
        EGFR exon 20 insertion mutations: clinicopathological characteristics and treatment outcomes in advanced non-small cell lung cancer.
        Clin Lung Cancer. 2021; 22: e859-e869
        • Ou S.-H.I.
        • Lin H.M.
        • Hong J.-L.
        • et al.
        Real-world response and outcomes in NSCLC patients with EGFR exon 20 insertion mutations.
        J Clin Oncol. 2021; 39: 9098
        • Saalfeld F.C.
        • Wenzel C.
        • Christopoulos P.
        • et al.
        Efficacy of immune checkpoint inhibitors alone or in combination with chemotherapy in NSCLC harboring ERBB2 mutations.
        J Thorac Oncol. 2021; 16: 1952-1958
        • Jänne P.A.
        • Wu Y.-L.
        • Kato T.
        • et al.
        1412TiP Mobocertinib (TAK-788) as first-line treatment vs platinum-based chemotherapy (CT) for NSCLC with EGFR exon 20 insertions (exon20ins).
        Ann Oncol. 2020; 31: S892-S893
        • Spira A.
        • Ramalingam S.
        • Neal J.
        • et al.
        OA15.01 mobocertinib in EGFR exon 20 insertion–positive metastatic NSCLC patients with disease control on prior EGFR TKI therapy.
        J Thorac Oncol. 2021; 16: S873-S874
        • Ou S.-H.
        • Lin H.M.
        • Hong J.-L.
        • et al.
        1211P Indirect comparison of mobocertinib and standard of care in platinum-pretreated patients with NSCLC with EGFR exon 20 insertion.
        Ann Oncol. 2021; 32: S964-S965
        • Minchom A.R.
        • Girard N.
        • Bazhenova L.
        • et al.
        Amivantamab compared with real-world therapies in patients with NSCLC with EGFR Exon 20 insertion mutations who have progressed after platinum doublet chemotherapy.
        J Clin Oncol. 2021; 39: 9052
        • Kron A.
        • Alidousty C.
        • Scheffler M.
        • et al.
        Impact of TP53 mutation status on systemic treatment outcome in ALK-rearranged non-small-cell lung cancer.
        Ann Oncol. 2018; 29: 2068-2075
        • Christopoulos P.
        • Kirchner M.
        • Bozorgmehr F.
        • et al.
        Identification of a highly lethal V3+ TP53+ subset in ALK+ lung adenocarcinoma.
        Int J Cancer. 2019; 144: 190-199
        • Christopoulos P.
        • Budczies J.
        • Kirchner M.
        • et al.
        Defining molecular risk in ALK+ NSCLC.
        Oncotarget. 2019; 10: 3093-3103
        • Ou S.
        • Hong J.
        • Lin H.
        • et al.
        MA14.01 distribution and detectability of EGFR exon 20 insertion variants in non–small cell lung cancer.
        J Thorac Oncol. 2021; 16: S928-S929
        • Lin J.J.
        • Cardarella S.
        • Lydon C.A.
        • et al.
        Five-year survival in EGFR-mutant metastatic lung adenocarcinoma treated with EGFR-TKIs.
        J Thorac Oncol. 2016; 11: 556-565
        • Zhou C.
        • Ramalingam S.
        • Li B.
        • et al.
        OA04.03 mobocertinib in NSCLC with EGFR exon 20 insertions: results from EXCLAIM and pooled platinum-pretreated patient populations.
        J Thorac Oncol. 2021; 16: S108
        • Huang L.-T.
        • Zhang S.-L.
        • Han C.-B.
        • Ma J.-T.
        Impact of EGFR exon 19 deletion subtypes on clinical outcomes in EGFR-TKI-Treated advanced non-small-cell lung cancer.
        Lung Cancer. 2022; 166: 9-16
        • Christopoulos P.
        • Kirchner M.
        • Endris V.
        • et al.
        EML4-ALK V3, treatment resistance, and survival: refining the diagnosis of ALK+ NSCLC.
        J Thorac Dis. 2018; 10: S1989-S1991
        • Giatromanolaki A.
        • Anestopoulos I.
        • Panayiotidis M.I.
        • et al.
        Prognostic relevance of the relative presence of CD4, CD8 and CD20 expressing tumor infiltrating lymphocytes in operable non-small cell lung cancer patients.
        Anticancer Res. 2021; 41: 3989-3995
        • Huang J.
        • Shen F.
        • Huang H.
        • et al.
        Th1 high in tumor microenvironment is an indicator of poor prognosis for patients with NSCLC.
        Oncotarget. 2017; 8: 13116-13125
        • Xiao M.
        • Wang C.
        • Zhang J.
        • et al.
        IFNgamma promotes papilloma development by up-regulating Th17-associated inflammation.
        Cancer Res. 2009; 69: 2010-2017
        • Medina-Echeverz J.
        • Haile L.A.
        • Zhao F.
        • et al.
        IFN-γ regulates survival and function of tumor-induced CD11b+ Gr-1high myeloid derived suppressor cells by modulating the anti-apoptotic molecule Bcl2a1.
        Eur J Immunol. 2014; 44: 2457-2467
        • Yamazaki K.
        • Yano T.
        • Kameyama T.
        • et al.
        Clinical significance of serum TH1/TH2 cytokines in patients with pulmonary adenocarcinoma.
        Surgery. 2002; 131: S236-S241
        • Magios N.
        • Bozorgmehr F.
        • Volckmar A.-L.
        • et al.
        Real-world implementation of sequential targeted therapies for EGFR-mutated lung cancer.
        Ther Adv Med Oncol. 2021; 131758835921996509